Methods for the Treatment of Abnormal Involuntary Movement Disorders

ABSTRACT

Disclosed herein are new dosage regimens for deuterium-substituted benzoquinoline compounds, and methods for the treatment of abnormal muscular activity, movement disorders, and related conditions.

This application is a continuation of U.S. application Ser. No.16/040,012, filed Jul. 19, 2018, which is a continuation of U.S.application Ser. No. 15/063,068, filed Mar. 7, 2016, now abandoned,which claims the benefit of priority of U.S. Provisional Application No.62/129,616, filed Mar. 6, 2015, No. 62/175,112, filed Jun. 12, 2015, andNo. 62/180,012, filed Jun. 15, 2015, the disclosures of each of which ishereby incorporated by reference as if written herein in its entirety.

Disclosed herein are new dosing regimens for deuterium-substitutedbenzoquinoline compounds, and methods for the treatment of abnormalinvoluntary movements, abnormal muscular activity, movement disorders,and related conditions.

Movement disorders are neurological conditions that affect the speed,fluency, quality, and ease of movement. Movement disorders can beclassified into two basic categories: those characterized by disorderedor excessive movement (referred to as “dyskinesia” and “hyperkinesia” or“hyperkinetic movement disorders,” respectively), and those that arecharacterized by slowness, or a lack of movement (referred to as“hypokinesia,” “bradykinesia,” or “akinesia”). An example of a“hyperkinetic” movement disorder is chorea, such as that associated withHuntington's disease (HD), while Parkinson's disease (PD) can beclassified as “hypokinetic,” because it is often characterized by slow,deliberate movements, or even freezing in place. Both hyperkinetic andhypokinetic movement disorders can severely affect a subject's qualityof life, making daily tasks difficult. Additionally, movement disorderscan cause a subject physical pain and increase the probability ofaccidents.

For example, chorea is an abnormal, involuntary, sudden movement thatcan affect all muscle groups and flow randomly from one body region toanother; like many abnormal involuntary movements, it is oftenalternatively referred to as a movement disorder. Chorea is a hallmarkof Huntington's Disease. In the United States, an estimated 30,000people have Huntington's disease. As many as 90% of patients with HDexperience chorea and it is moderate to severe in approximately 70% ofthese patients. It is considered by clinicians to be a seriouscondition, given its significant interference with daily functioning andincreased risk for injury to the patient. In its early stages, choreacan contribute to impaired speaking, writing, and activities of dailyliving such as feeding, dressing, and bathing. In its later stages,chorea can cause gait instability and poor postural control, with anincreased risk of serious injury from falling or from flailing intoobjects. Severity of chorea and parkinsonism has been shown to beindependently associated with falls in later-stage patients with HD.Dysphagia is a component of HD and can lead to recurrent aspirationpneumonia, weight loss, and behavioral problems.

The American Academy of Neurology's guideline indicates that,“Huntington's disease remains a devastating neurodegenerative disease inneed of neuroprotective and symptomatic treatments” and that “treatingchorea is an important part of Huntington's disease management.” Asurvey of 52 international experts indicated they would treat chorea forthe following reasons: 88% physical injury, 81% loss of balance, 77%social isolation, and 77% interference with work. Despite this guidance,patients with HD who have chorea are not often treated.

The only FDA-approved therapy in the United States for the treatment ofchorea associated with HD is tetrabenazine (XENAZINE®), an inhibitor ofVMAT2. Tetrabenazine reduces presynaptic concentrations of monoamines,such as dopamine, in neurons that regulate body movements. Althoughapproximately 30,000 people in the United States are affected by HD andapproximately 200,000 individuals may carry the gene and be at risk ofdeveloping HD, according to a November 2013 presentation by Lundbeck,only approximately 4,000 patients received this therapy. A substantialmajority of patients with chorea of HD are not receiving treatment withtetrabenazine. Furthermore, based on interviews with physicians in 2011,it is estimated that use of tetrabenazine in hyperkinetic movementdisorders other than the chorea of HD may account for up to half of itsuse, indicating that as few as 2,000 patients with HD are receivingtetrabenazine. Additionally, a report from the Baylor College ofMedicine indicated that only 78 of the 349 hyperkinetic movementdisorder patients treated with tetrabenazine between 2006 and 2009 werepatients with chorea. Clearly, a substantial need for effectivetreatments for movement disorders exists, and is only partially met byavailable therapies.

In addition to chorea, impairment in overall motor symptoms severelydisrupt day-to-day functioning. The National Institutes of NeurologicalDisorders and Stroke considers the Unified Huntington's Disease RatingScale (UHDRS) motor function assessments in the Total Motor Score (TMS)to be a core outcome in the evaluation of HD. All currently recruitinglarge Phase 2b/3 randomized clinical trials in patients with HD in theUnited States are using UHDRS-TMS as their primary endpoint. Significantcorrelations between the UHDRS-TMS and functional measures for sleep,rest, eating, work, recreation and past-times, ambulation, mobility,body care and movement, social interaction, communication, physical, andpsychosocial dimensions have been shown in patients with HD. HigherUHDRS-TMS scores are associated with a statistically significant lowerlikelihood of performing work, managing finances, driving safely,supervising children, and volunteering. Every 1-point worsening in theTMS was associated a 5% to 10% reduction in the likelihood of being ableto complete these certain tasks. The UHDRS-TMS is an independentpredictor of functional disability based on scales including the 36-ItemShort-Form Health Survey (SF-36).

Also in the United States, an estimated 500,000 patients have themovement disorder tardive dyskinesia and experience abnormal muscularactivity. Tardive dyskinesia is a hyperkinetic movement disorder thattypically manifests as rapid, repetitive, stereotypic movements that canbe induced by certain drugs, such as neuroleptics, such as dopaminereceptor blocking agents, which are used for treating psychiatricconditions, as well as by drugs such as metoclopramide, which are usedfor treating various gastrointestinal disorders. These patients aremanaged largely by psychiatrists and movement disorder neurologists, andthere are no FDA-approved treatments for tardive dyskinesia.

Also in the United States, an estimated 100,000 children have tics(abnormal involuntary movements or vocalizations) associated withTourette syndrome, with an estimated 27% categorized as moderate tosevere. Peak severity of the disorder is around 12 years of age, with anestimated 13% to 22% of affected children continuing to take medicationsfor tics as adults. Few new drugs have been introduced for treating atic associated with Tourette syndrome in more than 30 years;inadequacies can be identified in the two approved neuroleptics and onerecently-approved dopamine antagonist. For example, these treatmentscarry, among other adverse events, the risk of causing permanentneurologic deficits, such as tardive dyskinesia.

Accordingly, there remains a need for improved compositions, dosingregimens, and methods for the treatment of abnormal muscular activity,abnormal involuntary movement and other related disorders.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows change in mean chorea score observed in patients takingeither deutetrabenazine or placebo from the First-HD study.

FIG. 2 presents the mean change from baseline in swallowing disturbanceover time for deutetrabenazine and placebo (as determined byquestionnaire), demonstrating a significant improvement in swallowingwith deutetrabenazine treatment.

FIG. 3 presents the mean change from baseline in body weight (kg) overtime for deutetrabenazine and placebo from the First-HD study.

FIG. 4 shows the mean total behavior score (A), anxiety (B) andcompulsive behavior (C) for deutetrabenazine-treated subjects comparedwith the placebo group, from the First-HD study.

FIG. 5 shows change in mean chorea score observed in patients switchedfrom tetrabenazine to deutetrabenazine, and the mean daily dose oftetrabenazine or deutetrabenazine corresponding to the chorea score,from the ARC-HD study. In the figure, the asterisk (*) at week 8indicates p=0.0252.

FIG. 6 shows change in mean total motor score observed in patientsswitched from tetrabenazine to deutetrabenazine from the ARC-HD study.

FIG. 7 presents the mean change from baseline in swallowing disturbanceover time in patients switched from tetrabenazine to deutetrabenazine(as determined by questionnaire) from the ARC-HD study, demonstrating atrend toward improvement in swallowing with deutetrabenazine treatment.

FIG. 8 shows the open-label long-term data in tardive dyskinesiapatients from a tardive dyskinesia study as percent of treated subjectswho were much improved or very much improved on a seven-point Likertscale of Patient Global Impression of Change (PGIC) and Clinical GlobalImpression of Change (CGIC).

FIG. 9 shows the mean change in motor, vocal, and combined total ticscores in subjects treated in the pilot Tourette Syndrome study, frombaseline through the end of treatment at week 8 and washout at week 9.The top line (triangles) represents the vocal tic score; the middle linerepresents motor (squares) tic score, and the bottom line (diamonds)represents the total (combined motor and vocal) tic score. Treatmentwith deutetrabenazine lowered (improved) both motor and vocal tics.

FIG. 10 shows the change in the Tourette Syndrome Clinical GlobalImpression in subjects treated in the pilot Tourette Syndrome study,from baseline through week 8; improvement is measured by reduction inTS-CGI score.

FIG. 11 shows the Tourette Syndrome Patient Global Impression of Changein subjects treated in the pilot Tourette Syndrome study, at week 8;improvement is measured by positive increase in TS-PGIC score wherein,e.g., 1 indicates minimally improved; 2, much improved; and 3, very muchimproved.

DETAILED DESCRIPTION OF THE INVENTION

Disclosed herein is a method of treating abnormal involuntary movementin a subject, comprising:

-   -   a) administering to the subject an initial daily amount of a        deuterium substituted tetrabenazine comprising at least about 6        mg per day;    -   b) determining after about one week the degree of control of        abnormal involuntary movement achieved with the initial daily        amount and the tolerability of the initial daily amount;    -   c) increasing the daily amount of the deuterium substituted        tetrabenazine upward by 6 or more mg/day to a subsequent daily        amount if the degree of control of abnormal involuntary movement        is inadequate and the initial daily amount is tolerable;    -   d) optionally, repeating steps b) and c) until the degree of        control of abnormal involuntary movement is adequate and the        daily amount of the deuterium substituted tetrabenazine is        tolerable; and    -   e) if any subsequent amount is intolerable, decreasing the daily        amount downward by 6 or more mg/day to a subsequent daily        amount.

Also disclosed is a method of treating abnormal involuntary movement ina subject, comprising:

-   -   a) administering to the subject an initial daily amount of        deutetrabenazine of at least about 6 mg per day;    -   b) determining after about one week the degree of control of        abnormal involuntary movement achieved with the initial daily        amount and the tolerability of the initial daily amount;    -   c) increasing the daily amount of the deutetrabenazine upward by        6 mg/day to a subsequent daily amount if the abnormal        involuntary movement is not reduced and the initial daily amount        is tolerable;    -   d) after about one week, optionally, repeating steps b) and c)        provided that abnormal involuntary movement is reduced and the        daily amount of the deutetrabenazine is tolerable; and    -   e) if any subsequent amount is not tolerated, decreasing the        daily amount downward by at least 6 mg/day to a subsequent daily        amount.

In certain embodiments, the abnormal involuntary movement is caused by amovement disorder.

In certain embodiments, the movement disorder is chosen from akathisia,akinesia, ataxia, athetosis, ballismus, bradykinesia, cerebral palsy,chorea, corticobasal degeneration, dyskinesias (e.g., paroxysmal),dystonia (general, segmental, or focal) including blepharospasm,writer's cramp (limb dystonia), laryngeal dystonia (spasmodicdysphonia), and oromandibular dystonia, essential tremor, geniospasm,hereditary spastic paraplegia, Huntington's Disease, multiple systematrophy (Shy Drager Syndrome), myoclonus, Parkinson's Disease,Parkinson's disease levodopa-induced dyskinesia, parkinsonism,progressive supranuclear palsy, restless legs syndrome, Rett Syndrome,spasmodic torticollis (cervical dystonia), spasticity due to stroke,cerebral palsy, multiple sclerosis, spinal cord or brain injury,stereotypic movement disorder, stereotypy, Sydenham's Chorea,synkinesis, tardive dyskinesia, tics, Tourette syndrome, and Wilson'sDisease.

In certain embodiments, the movement disorder is a hyperkinetic movementdisorder.

In certain embodiments, the abnormal involuntary movement is chosen fromchorea, akathisia, dyskinesia, tremor, and tic.

In certain embodiments, the abnormal involuntary movement is chorea. Incertain embodiments, the abnormal involuntary movement is choreaassociated with Huntington's disease. In certain embodiments, theabnormal involuntary movement is a tic. In certain embodiments, theabnormal involuntary movement is a tic associated with Tourettesyndrome.

In certain embodiments, movement disorder is chosen from Huntington'sdisease, tardive dyskinesia, tics associated with Tourette syndrome,dystonia, and Parkinson's disease levodopa-induced dyskinesia.

In certain embodiments, the movement disorder is chosen fromHuntington's disease, tardive dyskinesia, and Tourette syndrome.

In certain embodiments, the movement disorder is Huntington's disease.

In certain embodiments, the movement disorder is chorea associated withHuntington's disease.

In certain embodiments, the absence of a reduction or suspension in aninitial or subsequent daily amount indicates that the daily amount istolerable. In certain embodiments, the tolerability is determined byassessment of one or more of the subject's levels of depression,anxiety, insomnia, somnolence, fatigue, dizziness, restlessness,agitation, irritability, akathisia, tardive dyskinesia, swallowing,parkinsonism, vomiting and nausea. In certain embodiments, a dose is nottolerated if one or more of the foregoing occur. In certain embodiments,a dose is not tolerated if somnolence or dizziness occur.

In certain embodiments, the deuterium substituted tetrabenazine isdeutetrabenazine. In certain embodiments, the deutetrabenazine is a plusisomeric form of deutetrabenazine. In certain embodiments, the plusisomeric form of deutetrabenazine is an alpha isomer. In certainembodiments, the VMAT2 inhibitor is a plus isomeric form oftetrabenazine. In certain embodiments, the plus isomeric form oftetrabenazine is an alpha isomer.

In certain embodiments, the initial daily amount of deutetrabenazine isabout 30% to about 70% of an existing total daily amount oftetrabenazine that provides adequate control of the abnormal involuntarymovement. In certain embodiments, the initial daily amount ofdeutetrabenazine is about 40% to about 60% of an existing total dailyamount of tetrabenazine that provides adequate control of the abnormalinvoluntary movement. In certain embodiments, the initial daily amountof deutetrabenazine is about 45% to about 55% of an existing total dailyamount of tetrabenazine that provides adequate control of the abnormalinvoluntary movement. In certain embodiments, the initial daily amountof deutetrabenazine is about 30% to about 50% of an existing total dailyamount of tetrabenazine that provides adequate control of the abnormalinvoluntary movement.

In certain embodiments, the daily amount of deutetrabenazine isadministered in one dose or two doses.

In certain embodiments, the initial daily amount of deutetrabenazine ischosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30mg, about 36 mg, about 42 mg, about 48 mg, about 54 mg, about 60 mg,about 66 mg, about 72 mg, and about 78 mg. In certain embodiments, theinitial daily amount of deutetrabenazine is chosen from about 6 mg,about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about42 mg, and about 48 mg.

In certain embodiments, the initial daily amount of deutetrabenazine isadministered in two doses, consisting of a first dose and a second dose.

In certain embodiments:

the first dose about 6 mg and the second dose is about 6 mg;

the first dose about 9 mg and the second dose is about 9 mg;

the first dose about 12 mg and the second dose is about 12 mg;

the first dose about 15 mg and the second dose is about 15 mg;

the first dose about 18 mg and the second dose is about 18 mg;

the first dose about 21 mg and the second dose is about 21 mg;

the first dose about 24 mg and the second dose is about 24 mg;

the first dose about 27 mg and the second dose is about 27 mg;

the first dose about 30 mg and the second dose is about 30 mg;

the first dose about 33 mg and the second dose is about 33 mg;

the first dose about 36 mg and the second dose is about 36 mg; and

the first dose about 39 mg and the second dose is about 39 mg.

In certain embodiments:

the first dose about 6 mg and the second dose is about 6 mg;

the first dose about 9 mg and the second dose is about 9 mg;

the first dose about 12 mg and the second dose is about 12 mg;

the first dose about 15 mg and the second dose is about 15 mg;

the first dose about 18 mg and the second dose is about 18 mg;

the first dose about 21 mg and the second dose is about 21 mg; and

the first dose about 24 mg and the second dose is about 24 mg.

In certain embodiments, the daily amount of deutetrabenazine is about 6mg to about 78 mg. In certain embodiments, the daily amount ofdeutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg,about 24 mg, about 30 mg, about 36 mg, about 42 mg, about 48 mg, about54 mg, about 60 mg, about 66 mg, about 72 mg, and about 78 mg. Incertain embodiments, the daily amount of deutetrabenazine is chosen fromabout 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36mg, about 42 mg, and about 48 mg.

In certain embodiments, the daily amount of deutetrabenazineadministered is less than or equal to about 48 mg, or less than or equalto about 36 mg for a subject concurrently receiving a strong CYP2D6inhibitor. In certain embodiments, the strong CYP2D6 inhibitor is chosenfrom fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, andritonavir. In certain embodiments, the strong CYP2D6 inhibitor is chosenfrom paroxetine, fluoxetine, and bupropion.

In certain embodiments, the degree of chorea control is improved by areduction of at least 0.5 points on the Total Maximal Chorea (TMC)score. In certain embodiments, the reduction in TMC score is at least 1point. In certain embodiments, the reduction in TMC score is at least1.5 points. In certain embodiments, the reduction in TMC score is atleast 2.0 points. In certain embodiments, the reduction in TMC score isat least 2.5 points. In certain embodiments, the improvement is over apre-treatment, “baseline” TMC score of at least 8.0. In certainembodiments, the improvement is over a pre-treatment, “baseline” TMCscore of at least 10.0. In certain embodiments, the improvement is overa pre-treatment, “baseline” TMC score of at least 12.0. In certainembodiments, the improvement is over a pre-treatment, “baseline” TMCscore of at least 12.7. In certain embodiments, the improvement is overa pre-treatment, “baseline” TMC score of at least 14.0.

In certain embodiments, chorea is reduced by at least 10%. In certainembodiments, chorea is reduced by at least 15%. In certain embodiments,chorea is reduced by at least 20%.

In certain embodiments, motor function is improved. In certainembodiments, motor function is improved by a reduction of at least 1point on the Total Motor Score (TMS). In certain embodiments, thereduction in TMS score is at least 2 points. In certain embodiments, thereduction in TMS score is at least 3 points. In certain embodiments, thereduction in TMS score is at least 4 points.

In certain embodiments, dystonia is improved. In certain embodiments,gait is improved. In certain embodiments, postural instability isalleviated. In certain embodiments, treatment reduces the symptoms ofparkinsonism.

In certain embodiments, the treatment does not worsen balance. Incertain embodiments, the treatment improves balance.

In certain embodiments, the treatment improves physical functioning. Incertain embodiments, the subject's physical functioning is improved asmeasured by the SF-36 physical functioning scale. In certainembodiments, the subject's physical functioning is improved as measuredby the SF-36 physical functioning scale from baseline. In certainembodiments, the subject's physical functioning is improved as measuredby the SF-36 physical functioning scale compared to untreated subjects.

In certain embodiments, the subject is much improved on the PGIC scale.In certain embodiments, the subject is very much improved on the PGICscale. In certain embodiments, the subject is much improved on the CGICscale. In certain embodiments, the subject is very much improved on theCGIC scale. In certain embodiments, the subject is much improved on thePGIC and CGIC scales. In certain embodiments, the subject is very muchimproved on the PGIC and CGIC scales.

In certain embodiments, the treatment improves swallowing.

In certain embodiments, treatment causes no significant increase ininsomnia, depression, anxiety, agitation, suicidal ideation, akathisia,irritability, or fatigue.

In certain embodiments, treatment causes no significant symptoms ofparkinsonism or dysphagia.

In certain embodiments, the treatment does not significantly prolong theQT interval. In certain embodiments, the treatment does notsignificantly change the QTcF value. In certain embodiments, the maximalincreases in QTcF is less than 5 ms.

Also provided are embodiments wherein any embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive. As used herein, two embodimentsare “mutually exclusive” when one is defined to be something whichcannot overlap with the other. Also provided is the use ofdeutetrabenazine for treating abnormal involuntary movement in asubject, as set forth herein or in any of the embodiments above. Alsoprovided is the use of deutetrabenazine in the manufacture of amedicament for treating abnormal involuntary movement in a subject, asset forth herein or in any of the embodiments above. Also provided is acomposition comprising deutetrabenazine for treating abnormalinvoluntary movement in a subject, as set forth herein or in any of theembodiments above.

Also provided is a method of transitioning a subject receiving anexisting total daily amount of tetrabenazine for control of abnormalinvoluntary movement, comprising:

-   -   a) administering to the subject an initial daily amount of a        deuterium substituted tetrabenazine which is about 30% to about        70% of the existing total daily amount of tetrabenazine and is        at least about 6 mg per day;    -   b) concurrently discontinuing the daily amount of tetrabenazine;    -   c) optionally, after about one week, determining the degree of        control of abnormal involuntary movement achieved with the        initial daily amount of a deuterium substituted tetrabenazine        and the tolerability of the initial amount;    -   d) optionally, if the degree of control of abnormal involuntary        movement is comparable to the control when the subject was        receiving tetrabenazine or inadequate and the initial amount is        tolerable, increasing the daily amount upward by 6 or more        mg/day to a subsequent daily amount;    -   e) optionally, repeating steps c) and d) until the degree of        control of abnormal involuntary movement is improved and the        initial amount is tolerable; and    -   f) optionally, if any subsequent amount is intolerable,        decreasing the daily amount downward by 6 or more mg/day to a        subsequent daily amount.

Also provided is a method of transitioning a subject receiving anexisting daily amount of tetrabenazine for control of abnormalinvoluntary movement from tetrabenazine to deutetrabenazine, comprising:

-   -   a) discontinuing the daily amount of tetrabenazine;    -   b) the next day, administering to the subject an initial daily        amount of deutetrabenazine, which is about 30% to about 70% of        the existing total daily amount of tetrabenazine and is at least        about 6 mg per day;    -   c) after about one week, determining the degree of control of        abnormal involuntary movement achieved with the initial daily        amount of a deuterium substituted tetrabenazine and the        tolerability of the initial amount;    -   d) if the degree of control of abnormal involuntary movement is        comparable to the control when the subject was receiving        tetrabenazine or inadequate and the initial amount is tolerated,        increasing the daily amount upward by 6 mg/day to a subsequent        daily amount of deutetrabenazine;    -   e) after about one week, optionally, repeating steps c) and d)        provided that abnormal involuntary movement is reduced and the        amount is tolerated; and    -   f) optionally, if any subsequent amount is not tolerated,        decreasing the daily amount downward by 6 mg/day to a subsequent        daily amount.

In certain embodiments, the initial daily amount of deutetrabenazine isabout 40% to about 60% of the existing total daily amount oftetrabenazine and is at least about 6 mg per day. In certainembodiments, the initial daily amount of deutetrabenazine is about 45%to about 55% of the existing total daily amount of tetrabenazine and isat least about 6 mg per day. In certain embodiments, the initial dailyamount of deutetrabenazine is about 30% to about 50% of the existingtotal daily amount of tetrabenazine and is at least about 6 mg per day.

In certain embodiments, the abnormal involuntary movement is caused by amovement disorder.

In certain embodiments, the movement disorder is chosen from akathisia,akinesia, ataxia, athetosis, ballismus, bradykinesia, cerebral palsy,chorea, corticobasal degeneration, dyskinesias (e.g., paroxysmal),dystonia (general, segmental, or focal) including blepharospasm,writer's cramp (limb dystonia), laryngeal dystonia (spasmodicdysphonia), and oromandibular dystonia, essential tremor, geniospasm,hereditary spastic paraplegia, Huntington's Disease, multiple systematrophy (Shy Drager Syndrome), myoclonus, Parkinson's Disease,Parkinson's disease levodopa-induced dyskinesia, parkinsonism,progressive supranuclear palsy, restless legs syndrome, Rett Syndrome,spasmodic torticollis (cervical dystonia), spasticity due to stroke,cerebral palsy, multiple sclerosis, spinal cord or brain injury,stereotypic movement disorder, stereotypy, Sydenham's Chorea,synkinesis, tardive dyskinesia, tics, Tourette syndrome, and Wilson'sDisease.

In certain embodiments, the movement disorder is a hyperkinetic movementdisorder.

In certain embodiments, the abnormal involuntary movement is chosen fromchorea, akathisia, dyskinesia, tremor, and tic.

In certain embodiments, the abnormal involuntary movement is chorea. Incertain embodiments, the abnormal involuntary movement is choreaassociated with Huntington's disease. In certain embodiments, theabnormal involuntary movement is a tic. In certain embodiments, theabnormal involuntary movement is a tic associated with Tourettesyndrome.

In certain embodiments, movement disorder is chosen from Huntington'sdisease, tardive dyskinesia, tics associated with Tourette syndrome,dystonia, and Parkinson's disease levodopa-induced dyskinesia.

In certain embodiments, the movement disorder is chosen fromHuntington's disease, tardive dyskinesia, and Tourette syndrome.

In certain embodiments, the movement disorder is Huntington's disease.

In certain embodiments, the movement disorder is chorea associated withHuntington's disease.

In certain embodiments, the absence of a reduction or suspension in aninitial or subsequent daily amount indicates that the daily amount istolerable. In certain embodiments, the tolerability is determined byassessment of one or more of the subject's levels of depression,anxiety, insomnia, somnolence, fatigue, dizziness, restlessness,agitation, irritability, akathisia, tardive dyskinesia, swallowing,parkinsonism, vomiting and nausea. In certain embodiments, a dose is nottolerated if one or more of the foregoing occur. In certain embodiments,a dose is not tolerated if somnolence or dizziness occur.

In certain embodiments, the deuterium substituted tetrabenazine isdeutetrabenazine. In certain embodiments, the deutetrabenazine is a plusisomeric form of deutetrabenazine. In certain embodiments, the plusisomeric form of deutetrabenazine is an alpha isomer. In certainembodiments, the VMAT2 inhibitor is a plus isomeric form oftetrabenazine. In certain embodiments, the plus isomeric form oftetrabenazine is an alpha isomer.

In certain embodiments, the daily amount of deutetrabenazine isadministered in one dose or two doses.

In certain embodiments, the initial daily amount of deutetrabenazine ischosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30mg, about 36 mg, about 42 mg, about 48 mg, about 54 mg, about 60 mg,about 66 mg, about 72 mg, and about 78 mg. In certain embodiments, theinitial daily amount of deutetrabenazine is chosen from about 6 mg,about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about42 mg, and about 48 mg. In certain embodiments, the daily amount ofdeutetrabenazine is about 6 mg to about 78 mg. In certain embodiments,the daily amount of deutetrabenazine is chosen from about 6 mg, about 12mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg,about 48 mg, about 54 mg, about 60 mg, about 66 mg, about 72 mg, andabout 78 mg. In certain embodiments, the daily amount ofdeutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg,about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about 48 mg.

In certain embodiments, the initial daily amount of deutetrabenazine isadministered in two doses, consisting of a first dose and a second dose.

In certain embodiments:

the first dose about 6 mg and the second dose is about 6 mg;

the first dose about 9 mg and the second dose is about 9 mg;

the first dose about 12 mg and the second dose is about 12 mg;

the first dose about 15 mg and the second dose is about 15 mg;

the first dose about 18 mg and the second dose is about 18 mg;

the first dose about 21 mg and the second dose is about 21 mg;

the first dose about 24 mg and the second dose is about 24 mg;

the first dose about 27 mg and the second dose is about 27 mg;

the first dose about 30 mg and the second dose is about 30 mg;

the first dose about 33 mg and the second dose is about 33 mg;

the first dose about 36 mg and the second dose is about 36 mg; and

the first dose about 39 mg and the second dose is about 39 mg.

In certain embodiments:

the first dose about 6 mg and the second dose is about 6 mg;

the first dose about 9 mg and the second dose is about 9 mg;

the first dose about 12 mg and the second dose is about 12 mg;

the first dose about 15 mg and the second dose is about 15 mg;

the first dose about 18 mg and the second dose is about 18 mg;

the first dose about 21 mg and the second dose is about 21 mg; and

the first dose about 24 mg and the second dose is about 24 mg.

In certain embodiments:

-   -   the existing total daily amount of tetrabenazine is about 12.5        mg and the initial daily amount of deutetrabenazine is about 6        mg;    -   the existing total daily amount of tetrabenazine is about 25 mg        and the initial daily amount of deutetrabenazine is about 12 mg;    -   the existing total daily amount of tetrabenazine is about 37.5        mg and the initial daily amount of deutetrabenazine is about 18        mg;    -   the existing total daily amount of tetrabenazine is about 50 mg        and the initial daily amount of deutetrabenazine is about 24 mg;    -   the existing total daily amount of tetrabenazine is about 62.5        mg and the initial daily amount of deutetrabenazine is about 30        mg;    -   the existing total daily amount of tetrabenazine is about 75 mg        and the initial daily amount of deutetrabenazine is about 36 mg;    -   the existing total daily amount of tetrabenazine is about 87.5        mg and the initial daily amount of deutetrabenazine is about 42        mg; or    -   the existing total daily amount of tetrabenazine is about 100 mg        and the initial daily amount of deutetrabenazine is about 48 mg.

In certain embodiments, the daily amount of deutetrabenazine is about 6mg to about 78 mg. In certain embodiments, the daily amount ofdeutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg,about 24 mg, about 30 mg, about 36 mg, about 42 mg, about 48 mg, about54 mg, about 60 mg, about 66 mg, about 72 mg, and about 78 mg. Incertain embodiments, the daily amount of deutetrabenazine is chosen fromabout 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36mg, about 42 mg, and about 48 mg.

In certain embodiments, the daily amount of deutetrabenazineadministered is less than or equal to about 48 mg, or less than or equalto about 36 mg for subjects concurrently receiving a strong CYP2D6inhibitor. In certain embodiments, the strong CYP2D6 inhibitor is chosenfrom fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, andritonavir. In certain embodiments, the strong CYP2D6 inhibitor is chosenfrom paroxetine, fluoxetine, and bupropion.

In certain embodiments, the chorea control is improved by a reduction ofat least 0.5 points on the Total Maximal Chorea (TMC) score. In certainembodiments, the reduction in TMC score is at least 1 point. In certainembodiments, the reduction in TMC score is at least 1.5 points. Incertain embodiments, the reduction in TMC score is at least 2.0 points.In certain embodiments, the reduction in TMC score is at least 2.5points. In certain embodiments, the improvement is over a pre-treatment,“baseline” TMC score of at least 8.0. In certain embodiments, theimprovement is over a pre-treatment, “baseline” TMC score of at least10.0. In certain embodiments, the improvement is over a pre-treatment,“baseline” TMC score of at least 12.0. In certain embodiments, theimprovement is over a pre-treatment, “baseline” TMC score of at least12.7. In certain embodiments, the improvement is over a pre-treatment,“baseline” TMC score of at least 14.0.

In certain embodiments, chorea is reduced by at least 10%. In certainembodiments, chorea is reduced by at least 15%. In certain embodiments,chorea is reduced by at least 20%.

In certain embodiments, motor function is improved.

In certain embodiments, motor function is improved by a reduction of atleast 1 point on the Total Motor Score (TMS). In certain embodiments,the reduction in TMS score is at least 2 points. In certain embodiments,the reduction in TMS score is at least 3 points. In certain embodiments,the reduction in TMS score is at least 4 points.

In certain embodiments, dystonia is improved. In certain embodiments,gait is improved. In certain embodiments, postural instability isalleviated. In certain embodiments, treatment reduces the symptoms ofparkinsonism.

In certain embodiments, the treatment does not worsen the subject'sbalance. In certain embodiments, the treatment improves balance.

In certain embodiments, the treatment improves physical functioning. Incertain embodiments, the subject's physical functioning is improved asmeasured by the SF-36 physical functioning scale. In certainembodiments, the subject's physical functioning is improved as measuredby the SF-36 physical functioning scale from baseline. In certainembodiments, the subject's physical functioning is improved as measuredby the SF-36 physical functioning scale compared to untreated subjects.

In certain embodiments, the subject is much improved on the PGIC scale.In certain embodiments, the subject is very much improved on the PGICscale. In certain embodiments, the subject is much improved on the CGICscale. In certain embodiments, the subject is very much improved on theCGIC scale. In certain embodiments, the subject is much improved on thePGIC and CGIC scales. In certain embodiments, the subject is very muchimproved on the PGIC and CGIC scales.

In certain embodiments, the treatment improves swallowing.

In certain embodiments, treatment causes no significant increase ininsomnia, depression, anxiety, agitation, suicidal ideation, akathisia,irritability, or fatigue.

In certain embodiments, treatment causes no significant parkinsonism ordysphagia.

In certain embodiments, the treatment does not significantly prolong theQT interval. In certain embodiments, the treatment does notsignificantly change the QTcF value. In certain embodiments, the maximalincreases in QTcF is less than 5 ms.

Also provided are embodiments wherein any embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive. Also provided is the use ofdeutetrabenazine for transitioning a subject receiving an existing totaldaily amount of tetrabenazine for control of abnormal involuntarymovement, as set forth herein or in any of the embodiments above. Alsoprovided is the use of deutetrabenazine in the manufacture of amedicament for transitioning a subject receiving an existing total dailyamount of tetrabenazine for control of abnormal involuntary movement, asset forth herein or in any of the embodiments above. Also provided is acomposition comprising deutetrabenazine for use in transitioning asubject receiving an existing total daily amount of tetrabenazine forcontrol of abnormal involuntary movement, as set forth herein or in anyof the embodiments above.

Also provided is a method of treating a movement disorder in a subjectcomprising the administration of a daily amount of a VMAT2 inhibitor,wherein either:

chorea is reduced by at least 10% and any one or more of the followingare true:

-   -   motor function is improved by at least 10%;    -   the subject's physical functioning is improved;    -   swallowing is improved;    -   balance is not worsened;    -   treatment causes no significant increase in insomnia,        depression, anxiety, agitation, suicidal ideation, akathisia,        irritability, fatigue, parkinsonism or dysphagia; and    -   the maximal increases in QTcF is less than 5 ms;

or motor function is improved by at least 10%, and any one or more ofthe following are true:

-   -   chorea is reduced by at least 10%;    -   the subject's physical functioning is improved;    -   swallowing is improved;    -   balance is not worsened;    -   treatment causes no significant increase in insomnia,        depression, anxiety, agitation, suicidal ideation, akathisia,        irritability, fatigue, parkinsonism or dysphagia; and

the maximal increases in QTcF is less than 5 ms.

In certain embodiments, the movement disorder is chosen from akathisia,akinesia, ataxia, athetosis, ballismus, bradykinesia, cerebral palsy,chorea, corticobasal degeneration, dyskinesias (e.g., paroxysmal),dystonia (general, segmental, or focal) including blepharospasm,writer's cramp (limb dystonia), laryngeal dystonia (spasmodicdysphonia), and oromandibular dystonia, essential tremor, geniospasm,hereditary spastic paraplegia, Huntington's Disease, multiple systematrophy (Shy Drager Syndrome), myoclonus, Parkinson's Disease,Parkinson's disease levodopa-induced dyskinesia, parkinsonism,progressive supranuclear palsy, restless legs syndrome, Rett Syndrome,spasmodic torticollis (cervical dystonia), spasticity due to stroke,cerebral palsy, multiple sclerosis, spinal cord or brain injury,stereotypic movement disorder, stereotypy, Sydenham's Chorea,synkinesis, tardive dyskinesia, tics, Tourette syndrome, and Wilson'sDisease.

In certain embodiments, the movement disorder is a hyperkinetic movementdisorder.

In certain embodiments, dystonia is improved. In certain embodiments,gait is improved. In certain embodiments, postural instability isalleviated. In certain embodiments, treatment reduces the symptoms ofparkinsonism.

In certain embodiments, the movement disorder is chosen fromHuntington's disease, tardive dyskinesia, and tics associated withTourette syndrome.

In certain embodiments, the movement disorder is Huntington's disease.In certain embodiments, the movement disorder is chorea associated withHuntington's disease.

In certain embodiments, the movement disorder is a tic. In certainembodiments, the movement disorder is a tic associated with Tourettesyndrome.

In certain embodiments, the VMAT2 inhibitor is a deuterium substitutedtetrabenazine. In certain embodiments, the deuterium substitutedtetrabenazine is deutetrabenazine. In certain embodiments, thedeutetrabenazine is a plus isomeric form of deutetrabenazine. In certainembodiments, the plus isomeric form of deutetrabenazine is an alphaisomer. In certain embodiments, the VMAT2 inhibitor is a plus isomericform of tetrabenazine. In certain embodiments, the plus isomeric form oftetrabenazine is an alpha isomer. In certain embodiments, the VMAT2inhibitor is valbenazine.

In certain embodiments, the daily amount of deutetrabenazine isadministered in one dose or two doses.

In certain embodiments, the daily amount of deutetrabenazine is about 6mg to about 78 mg. In certain embodiments, the daily amount ofdeutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg,about 24 mg, about 30 mg, about 36 mg, about 42 mg, about 48 mg, about54 mg, about 60 mg, about 66 mg, about 72 mg, and about 78 mg. Incertain embodiments, the daily amount of deutetrabenazine is chosen fromabout 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36mg, about 42 mg, and about 48 mg.

In certain embodiments, the daily amount of deutetrabenazine isadministered in two doses, consisting of a first dose and a second dose.

In certain embodiments:

the first dose about 6 mg and the second dose is about 6 mg;

the first dose about 9 mg and the second dose is about 9 mg;

the first dose about 12 mg and the second dose is about 12 mg;

the first dose about 15 mg and the second dose is about 15 mg;

the first dose about 18 mg and the second dose is about 18 mg;

the first dose about 21 mg and the second dose is about 21 mg;

the first dose about 24 mg and the second dose is about 24 mg;

the first dose about 27 mg and the second dose is about 27 mg;

the first dose about 30 mg and the second dose is about 30 mg;

the first dose about 33 mg and the second dose is about 33 mg;

the first dose about 36 mg and the second dose is about 36 mg; and

the first dose about 39 mg and the second dose is about 39 mg.

In certain embodiments:

the first dose about 6 mg and the second dose is about 6 mg;

the first dose about 9 mg and the second dose is about 9 mg;

the first dose about 12 mg and the second dose is about 12 mg;

the first dose about 15 mg and the second dose is about 15 mg;

the first dose about 18 mg and the second dose is about 18 mg;

the first dose about 21 mg and the second dose is about 21 mg; and

the first dose about 24 mg and the second dose is about 24 mg.

In certain embodiments, the daily amount of deutetrabenazine is about 6mg to about 78 mg. In certain embodiments, the daily amount ofdeutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg,about 24 mg, about 30 mg, about 36 mg, about 42 mg, about 48 mg, about54 mg, about 60 mg, about 66 mg, about 72 mg, and about 78 mg. Incertain embodiments, the daily amount of deutetrabenazine is chosen fromabout 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36mg, about 42 mg, and about 48 mg.

In certain embodiments, the daily amount of deutetrabenazineadministered is less than or equal to about 48 mg, or less than or equalto about 36 mg for subjects concurrently receiving a strong CYP2D6inhibitor. In certain embodiments, the strong CYP2D6 inhibitor is chosenfrom fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, andritonavir. In certain embodiments, the strong CYP2D6 inhibitor is chosenfrom paroxetine, fluoxetine, and bupropion.

In certain embodiments, the chorea control is improved by a reduction ofat least 0.5 points on the Total Maximal Chorea (TMC) score. In certainembodiments, the reduction in TMC score is at least 1 point. In certainembodiments, the reduction in TMC score is at least 1.5 points. Incertain embodiments, the reduction in TMC score is at least 2.0 points.In certain embodiments, the reduction in TMC score is at least 2.5points. In certain embodiments, the improvement is over a pre-treatment,“baseline” TMC score of at least 8.0. In certain embodiments, theimprovement is over a pre-treatment, “baseline” TMC score of at least10.0. In certain embodiments, the improvement is over a pre-treatment,“baseline” TMC score of at least 12.0. In certain embodiments, theimprovement is over a pre-treatment, “baseline” TMC score of at least12.7. In certain embodiments, the improvement is over a pre-treatment,“baseline” TMC score of at least 14.0.

In certain embodiments, chorea is reduced by at least 10%. In certainembodiments, chorea is reduced by at least 15%. In certain embodiments,chorea is reduced by at least 20%.

In certain embodiments, motor function is improved.

In certain embodiments, motor function is improved by a reduction of atleast 1 point on the Total Motor Score (TMS). In certain embodiments,the reduction in TMS score is at least 2 points. In certain embodiments,the reduction in TMS score is at least 3 points. In certain embodiments,the reduction in TMS score is at least 4 points.

In certain embodiments, dystonia is improved. In certain embodiments,gait is improved. In certain embodiments, postural instability isimproved. In certain embodiments, treatment reduces the symptoms ofparkinsonism.

In certain embodiments, the treatment does not worsen the subject'sbalance. In certain embodiments, the treatment improves balance.

In certain embodiments, the treatment improves physical functioning. Incertain embodiments, the subject's physical functioning is improved asmeasured by the SF-36 physical functioning scale. In certainembodiments, the subject's physical functioning is improved as measuredby the SF-36 physical functioning scale from baseline. In certainembodiments, the subject's physical functioning is improved as measuredby the SF-36 physical functioning scale compared to untreated subjects.

In certain embodiments, the subject is much improved on the PGIC scale.In certain embodiments, the subject is very much improved on the PGICscale. In certain embodiments, the subject is much improved on the CGICscale. In certain embodiments, the subject is very much improved on theCGIC scale. In certain embodiments, the subject is much improved on thePGIC and CGIC scales. In certain embodiments, the subject is very muchimproved on the PGIC and CGIC scales.

In certain embodiments, the treatment improves swallowing.

In certain embodiments, treatment causes no significant increase ininsomnia, depression, anxiety, agitation, suicidal ideation, akathisia,irritability, or fatigue.

In certain embodiments, treatment causes no significant parkinsonism ordysphagia.

In certain embodiments, the treatment does not significantly prolong theQT interval. In certain embodiments, the treatment does notsignificantly change the QTcF value. In certain embodiments, the maximalincreases in QTcF is less than 5 ms.

Also provided are embodiments as recited in any of the embodimentsabove, wherein either:

chorea is reduced by at least 10% and any two or more of the followingare true:

-   -   motor function is improved by at least 10%;    -   the subject's physical functioning is improved;    -   swallowing is improved;    -   balance is not worsened;    -   treatment causes no significant increase in insomnia,        depression, anxiety, agitation, suicidal ideation, akathisia,        irritability, fatigue, parkinsonism or dysphagia; and    -   the maximal increases in QTcF is less than 5 ms;

or motor function is improved by at least 10%, and any two or more ofthe following are true:

-   -   chorea is reduced by at least 10%;    -   the subject's physical functioning is improved;    -   swallowing is improved;    -   balance is not worsened;    -   treatment causes no significant increase in insomnia,        depression, anxiety, agitation,    -   suicidal ideation, akathisia, irritability, fatigue,        parkinsonism or dysphagia; and    -   the maximal increases in QTcF is less than 5 ms.

Also provided are embodiments as recited in any of the embodimentsabove, wherein either:

chorea is reduced by at least 10% and any three or more of the followingare true:

-   -   motor function is improved by at least 10%;    -   the subject's physical functioning is improved;    -   swallowing is improved;    -   balance is not worsened;    -   treatment causes no significant increase in insomnia,        depression, anxiety, agitation, suicidal ideation, akathisia,        irritability, fatigue, parkinsonism or dysphagia; and    -   the maximal increases in QTcF is less than 5 ms;

or motor function is improved by at least 10%, and any three or more ofthe following are true:

-   -   chorea is reduced by at least 10%;    -   the subject's physical functioning is improved;    -   swallowing is improved;    -   balance is not worsened;    -   treatment causes no significant increase in insomnia,        depression, anxiety, agitation, suicidal ideation, akathisia,        irritability, fatigue, parkinsonism or dysphagia; and    -   the maximal increases in QTcF is less than 5 ms.

Also provided are embodiments wherein any embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive. Also provided is the use of aVMAT2 inhibitor for treating a movement disorder in a subject, as setforth herein or in any of the embodiments above i. Also provided is theuse of a VMAT2 inhibitor in the manufacture of a medicament for treatinga movement disorder in a subject, as set forth herein or in any of theembodiments above. Also provided is a composition comprising a VMAT2inhibitor for use in treating a movement disorder in a subject, as setforth herein or in any of the embodiments above.

Also provided is a method of treating abnormal involuntary movement in asubject, comprising administering an initial daily amount of a VMAT2inhibitor to the subject, in a manner that:

-   -   a) adequately reduces the subject's abnormal involuntary        movement; and    -   b) improves one or more of the subject's symptoms of anxiety,        swallowing, body weight, irritability, overall behavior, and        compulsive behavior.

In further embodiments, the method comprises the additional steps of:

-   -   c) determining after about one week the degree of control of        abnormal involuntary movement achieved with the initial daily        amount and the tolerability of the initial daily amount; and    -   d) increasing the daily amount of the deuterium substituted        tetrabenazine upward by 6 or more mg/day to a subsequent daily        amount if the degree of control of abnormal involuntary movement        is inadequate and the initial daily amount is tolerable;    -   e) optionally, repeating steps b) and c) until the degree of        control of abnormal involuntary movement is adequate and the        daily amount of the deuterium substituted tetrabenazine is        tolerable; and    -   f) if any subsequent amount is intolerable, decreasing the daily        amount downward by 6 or more mg/day to a subsequent daily        amount.

Also provided is a method of treating abnormal involuntary movement in asubject, comprising administering a daily amount of deutetrabenazine tothe subject, which:

-   -   a) adequately reduces the subject's abnormal involuntary        movement; and    -   b) improves one or more of the subject's symptoms of depression,        insomnia, somnolence, fatigue, dizziness, restlessness,        agitation, akathisia, parkinsonism, nausea, anxiety, impaired        swallowing, body weight gain, irritability, and compulsive        behavior.

In certain embodiments, the method comprises the additional steps of:

-   -   c) determining after about one week of treatment the degree of        control of abnormal involuntary movement achieved with the daily        amount of deutetrabenazine (the initial daily amount) and the        tolerability of the initial daily amount; and    -   d) increasing the daily amount of the deuterium substituted        tetrabenazine upward by at least 6 mg/day to a subsequent daily        amount if abnormal involuntary movement is not reduced and the        initial daily amount is tolerated;    -   e) after one week, optionally, repeating steps b) and c)        provided that abnormal involuntary movement is reduced and the        daily amount of the deuterium substituted tetrabenazine is        tolerated; and    -   f) if any subsequent amount is not tolerated, decreasing the        daily amount downward by 6 mg/day to a subsequent daily amount.

In certain embodiments, the abnormal involuntary movement is a caused bya movement disorder.

In certain embodiments, the movement disorder is chosen from choreaassociated with Huntington's disease, tardive dyskinesia, a ticassociated with Tourette syndrome, dystonia, and Parkinson's diseaselevodopa-induced dyskinesia.

In certain embodiments, the movement disorder is chosen from choreaassociated with Huntington's disease, tardive dyskinesia, and ticsassociated with Tourette syndrome.

In certain embodiments, the movement disorder is chorea associated withHuntington's disease.

In certain embodiments, the abnormal muscular activity is a tic. Incertain embodiments, the abnormal muscular activity is a tic associatedwith Tourette syndrome.

In certain embodiments, the daily amount of deutetrabenazine improvesone or more of the subject's symptoms of anxiety, swallowing, bodyweight, irritability, overall behavior, and compulsive behavior. Incertain embodiments, the movement disorder is chorea associated withHuntington's disease, and the daily amount of deutetrabenazine improvesone or more of the subject's symptoms of depression, insomnia,somnolence, fatigue, dizziness, restlessness, agitation, akathisia,parkinsonism, nausea, anxiety, impaired swallowing, body weight gain,irritability, and compulsive behavior. In certain embodiments, themovement disorder is chosen from tardive dyskinesia and Tourettesyndrome, and the daily amount of deutetrabenazine improves one or moreof the subject's symptoms of depression, insomnia, somnolence, fatigue,dizziness, restlessness, agitation, akathisia, parkinsonism, nausea,anxiety, impaired swallowing, irritability, and compulsive behavior.

In certain embodiments, the absence of a reduction or suspension in aninitial or subsequent daily amount indicates that the daily amount istolerable. In certain embodiments, the tolerability is determined byassessment of one or more of the subject's levels of depression,anxiety, insomnia, somnolence, fatigue, dizziness, restlessness,agitation, irritability, akathisia, tardive dyskinesia, swallowing,parkinsonism, vomiting and nausea. In certain embodiments, a dose is nottolerated if one or more of the foregoing occur. In certain embodiments,a dose is not tolerated if somnolence or dizziness occur.

In certain embodiments, the VMAT2 inhibitor is a deuterium substitutedtetrabenazine. In certain embodiments, the deuterium substitutedtetrabenazine is deutetrabenazine. In certain embodiments, thedeutetrabenazine is a plus isomeric form of deutetrabenazine. In certainembodiments, the plus isomeric form of deutetrabenazine is an alphaisomer. In certain embodiments, the VMAT2 inhibitor is a plus isomericform of tetrabenazine. In certain embodiments, the plus isomeric form oftetrabenazine is an alpha isomer. In certain embodiments, the VMAT2inhibitor is valbenazine.

In certain embodiments, the daily amount of deutetrabenazine isadministered in one dose or two doses.

In certain embodiments, the initial daily amount of deutetrabenazine ischosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30mg, about 36 mg, about 42 mg, about 48 mg, about 54 mg, about 60 mg,about 66 mg, about 72 mg, and about 78 mg. In certain embodiments, theinitial daily amount of deutetrabenazine is chosen from about 6 mg,about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about42 mg, and about 48 mg.

In certain embodiments, the initial daily amount of deutetrabenazine isadministered in two doses, consisting of a first dose and a second dose.

In certain embodiments:

the first dose about 6 mg and the second dose is about 6 mg;

the first dose about 9 mg and the second dose is about 9 mg;

the first dose about 12 mg and the second dose is about 12 mg;

the first dose about 15 mg and the second dose is about 15 mg;

the first dose about 18 mg and the second dose is about 18 mg;

the first dose about 21 mg and the second dose is about 21 mg;

the first dose about 24 mg and the second dose is about 24 mg;

the first dose about 27 mg and the second dose is about 27 mg;

the first dose about 30 mg and the second dose is about 30 mg;

the first dose about 33 mg and the second dose is about 33 mg;

the first dose about 36 mg and the second dose is about 36 mg; and

the first dose about 39 mg and the second dose is about 39 mg.

In certain embodiments:

the first dose about 6 mg and the second dose is about 6 mg;

the first dose about 9 mg and the second dose is about 9 mg;

the first dose about 12 mg and the second dose is about 12 mg;

the first dose about 15 mg and the second dose is about 15 mg;

the first dose about 18 mg and the second dose is about 18 mg;

the first dose about 21 mg and the second dose is about 21 mg; and

the first dose about 24 mg and the second dose is about 24 mg.

In certain embodiments, the daily amount of deutetrabenazine is about 6mg to about 78 mg. In certain embodiments, the daily amount ofdeutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg,about 24 mg, about 30 mg, about 36 mg, about 42 mg, about 48 mg, about54 mg, about 60 mg, about 66 mg, about 72 mg, and about 78 mg. Incertain embodiments, the daily amount of deutetrabenazine is chosen fromabout 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36mg, about 42 mg, and about 48 mg.

In certain embodiments, the daily amount of deutetrabenazineadministered is less than or equal to about 48 mg, or less than or equalto about 36 mg for subjects concurrently receiving a strong CYP2D6inhibitor. In certain embodiments, the strong CYP2D6 inhibitor is chosenfrom fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, andritonavir. In certain embodiments, the strong CYP2D6 inhibitor is chosenfrom paroxetine, fluoxetine, and bupropion.

In certain embodiments, the chorea control is improved by a reduction ofat least 0.5 points on the Total Maximal Chorea (TMC) score. In certainembodiments, the reduction in TMC score is at least 1 point. In certainembodiments, the reduction in TMC score is at least 1.5 points. Incertain embodiments, the reduction in TMC score is at least 2.0 points.In certain embodiments, the reduction in TMC score is at least 2.5points. In certain embodiments, the improvement is over a pre-treatment,“baseline” TMC score of at least 8.0. In certain embodiments, theimprovement is over a pre-treatment, “baseline” TMC score of at least10.0. In certain embodiments, the improvement is over a pre-treatment,“baseline” TMC score of at least 12.0. In certain embodiments, theimprovement is over a pre-treatment, “baseline” TMC score of at least12.7. In certain embodiments, the improvement is over a pre-treatment,“baseline” TMC score of at least 14.0.

In certain embodiments, chorea is reduced by at least 10%. In certainembodiments, chorea is reduced by at least 15%. In certain embodiments,chorea is reduced by at least 20%.

In certain embodiments, motor function is improved.

In certain embodiments, motor function is improved by a reduction of atleast 1 point on the Total Motor Score (TMS). In certain embodiments,the reduction in TMS score is at least 2 points. In certain embodiments,the reduction in TMS score is at least 3 points. In certain embodiments,the reduction in TMS score is at least 4 points.

In certain embodiments, dystonia is improved. In certain embodiments,gait is improved. In certain embodiments, postural instability isimproved. In certain embodiments, treatment reduces the symptoms ofparkinsonism.

In certain embodiments, the treatment does not worsen the subject'sbalance. In certain embodiments, the treatment improves balance.

In certain embodiments, the treatment improves physical functioning. Incertain embodiments, the subject's physical functioning is improved asmeasured by the SF-36 physical functioning scale. In certainembodiments, the subject's physical functioning is improved as measuredby the SF-36 physical functioning scale from baseline. In certainembodiments, the subject's physical functioning is improved as measuredby the SF-36 physical functioning scale compared to untreated subjects.

In certain embodiments, the subject is much improved on the PGIC scale.In certain embodiments, the subject is very much improved on the PGICscale. In certain embodiments, the subject is much improved on the CGICscale. In certain embodiments, the subject is very much improved on theCGIC scale. In certain embodiments, the subject is much improved on thePGIC and CGIC scales. In certain embodiments, the subject is very muchimproved on the PGIC and CGIC scales.

In certain embodiments, the treatment improves swallowing.

In certain embodiments, treatment causes no significant increase ininsomnia, depression, anxiety, agitation, suicidal ideation, akathisia,irritability, or fatigue.

In certain embodiments, treatment causes no significant parkinsonism ordysphagia.

In certain embodiments, the treatment does not significantly prolong theQT interval. In certain embodiments, the treatment does notsignificantly change the QTcF value. In certain embodiments, the maximalincreases in QTcF is less than 5 ms.

Also provided are embodiments wherein any embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive. Also provided is the use of aVMAT2 inhibitor for treating abnormal involuntary movement in a subject,as set forth herein or in any of the embodiments above i. Also providedis the use of a VMAT2 inhibitor in the manufacture of a medicament fortreating abnormal involuntary movement in a subject, as set forth hereinor in any of the embodiments above. Also provided is a compositioncomprising a VMAT2 inhibitor for use in treating abnormal involuntarymovement in a subject, as set forth herein or in any of the embodimentsabove.

Also provided is a method of reducing chorea and improving motorfunction in a subject with Huntington's disease, comprising theadministration of a daily amount of a VMAT2 inhibitor.

In certain embodiments, the VMAT2 inhibitor is a deuterium substitutedtetrabenazine. In certain embodiments, the deuterium substitutedtetrabenazine is deutetrabenazine. In certain embodiments, thedeutetrabenazine is a plus isomeric form of deutetrabenazine. In certainembodiments, the plus isomeric form of deutetrabenazine is an alphaisomer. In certain embodiments, the VMAT2 inhibitor is a plus isomericform of tetrabenazine. In certain embodiments, the plus isomeric form oftetrabenazine is an alpha isomer. In certain embodiments, the VMAT2inhibitor is valbenazine.

In certain embodiments, the daily amount of deutetrabenazine isadministered in one dose or two doses.

In certain embodiments, the daily amount of deutetrabenazine is chosenfrom about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg,about 36 mg, about 42 mg, about 48 mg, about 54 mg, about 60 mg, about66 mg, about 72 mg, and about 78 mg. In certain embodiments, the dailyamount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about 48mg.

In certain embodiments, the daily amount of deutetrabenazine isadministered in two doses, consisting of a first dose and a second dose.

In certain embodiments:

the first dose about 6 mg and the second dose is about 6 mg;

the first dose about 9 mg and the second dose is about 9 mg;

the first dose about 12 mg and the second dose is about 12 mg;

the first dose about 15 mg and the second dose is about 15 mg;

the first dose about 18 mg and the second dose is about 18 mg;

the first dose about 21 mg and the second dose is about 21 mg;

the first dose about 24 mg and the second dose is about 24 mg;

the first dose about 27 mg and the second dose is about 27 mg;

the first dose about 30 mg and the second dose is about 30 mg;

the first dose about 33 mg and the second dose is about 33 mg;

the first dose about 36 mg and the second dose is about 36 mg; and

the first dose about 39 mg and the second dose is about 39 mg.

In certain embodiments:

the first dose about 6 mg and the second dose is about 6 mg;

the first dose about 9 mg and the second dose is about 9 mg;

the first dose about 12 mg and the second dose is about 12 mg;

the first dose about 15 mg and the second dose is about 15 mg;

the first dose about 18 mg and the second dose is about 18 mg;

the first dose about 21 mg and the second dose is about 21 mg; and

the first dose about 24 mg and the second dose is about 24 mg.

In certain embodiments, the daily amount of deutetrabenazine is about 6mg to about 78 mg. In certain embodiments, the daily amount ofdeutetrabenazine administered is less than or equal to about 48 mg, orless than or equal to about 36 mg for subjects concurrently receiving astrong CYP2D6 inhibitor. In certain embodiments, the strong CYP2D6inhibitor is chosen from fluoxetine, paroxetine, bupropion, quinidine,cinacalcet, and ritonavir. In certain embodiments, the strong CYP2D6inhibitor is chosen from paroxetine, fluoxetine, and bupropion.

In certain embodiments, the chorea control is improved by a reduction ofat least 0.5 points on the Total Maximal Chorea (TMC) score. In certainembodiments, the reduction in TMC score is at least 1 point. In certainembodiments, the reduction in TMC score is at least 1.5 points. Incertain embodiments, the reduction in TMC score is at least 2.0 points.In certain embodiments, the reduction in TMC score is at least 2.5points. In certain embodiments, the improvement is over a pre-treatment,“baseline” TMC score of at least 8.0. In certain embodiments, theimprovement is over a pre-treatment, “baseline” TMC score of at least10.0. In certain embodiments, the improvement is over a pre-treatment,“baseline” TMC score of at least 12.0. In certain embodiments, theimprovement is over a pre-treatment, “baseline” TMC score of at least12.7. In certain embodiments, the improvement is over a pre-treatment,“baseline” TMC score of at least 14.0.

In certain embodiments, chorea is reduced by at least 10%. In certainembodiments, chorea is reduced by at least 15%. In certain embodiments,chorea is reduced by at least 20%.

In certain embodiments, motor function is improved.

In certain embodiments, motor function is improved by a reduction of atleast 1 point on the Total Motor Score (TMS). In certain embodiments,the reduction in TMS score is at least 2 points. In certain embodiments,the reduction in TMS score is at least 3 points. In certain embodiments,the reduction in TMS score is at least 4 points.

In certain embodiments, dystonia is improved. In certain embodiments,gait is improved. In certain embodiments, postural instability isimproved. In certain embodiments, treatment reduces the symptoms ofparkinsonism.

In certain embodiments, the treatment does not worsen the subject'sbalance. In certain embodiments, the treatment improves balance.

In certain embodiments, the treatment improves physical functioning. Incertain embodiments, the subject's physical functioning is improved asmeasured by the SF-36 physical functioning scale. In certainembodiments, the subject's physical functioning is improved as measuredby the SF-36 physical functioning scale from baseline. In certainembodiments, the subject's physical functioning is improved as measuredby the SF-36 physical functioning scale compared to untreated subjects.

In certain embodiments, the subject is much improved on the PGIC scale.In certain embodiments, the subject is very much improved on the PGICscale. In certain embodiments, the subject is much improved on the CGICscale. In certain embodiments, the subject is very much improved on theCGIC scale. In certain embodiments, the subject is much improved on thePGIC and CGIC scales. In certain embodiments, the subject is very muchimproved on the PGIC and CGIC scales.

In certain embodiments, the treatment improves swallowing.

In certain embodiments, treatment causes no significant increase ininsomnia, depression, anxiety, agitation, suicidal ideation, akathisia,irritability, or fatigue.

In certain embodiments, treatment causes no significant parkinsonism ordysphagia.

In certain embodiments, the treatment does not significantly prolong theQT interval. In certain embodiments, the treatment does notsignificantly change the QTcF value. In certain embodiments, the maximalincreases in QTcF is less than 5 ms.

Also provided are embodiments wherein any embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive. Also provided is the use of aVMAT2 inhibitor for chorea and improving motor function in a subjectwith Huntington's disease, as set forth herein or in any of theembodiments above. Also provided is the use of a VMAT2 inhibitor in themanufacture of a medicament for chorea and improving motor function in asubject with Huntington's disease, as set forth herein or in any of theembodiments above. Also provided is a composition comprising a VMAT2inhibitor for use in chorea and improving motor function in a subjectwith Huntington's disease, as set forth herein or in any of theembodiments above.

Also provided is a method of improving motor function in a subject withHuntington's disease, tardive dyskinseia, or Tourette syndrome,comprising the administration of about a daily amount of a VMAT2inhibitor. In certain embodiments, the VMAT2 inhibitor is a deuteriumsubstituted tetrabenazine.

In certain embodiments, the subject has Huntington's disease. In certainembodiments, the subject has tardive dyskinseia. In certain embodiments,the subject has Tourette syndrome.

In certain embodiments, the deuterium substituted tetrabenazine isdeutetrabenazine. In certain embodiments, the deutetrabenazine is a plusisomeric form of deutetrabenazine. In certain embodiments, the plusisomeric form of deutetrabenazine is an alpha isomer. In certainembodiments, the VMAT2 inhibitor is a plus isomeric form oftetrabenazine. In certain embodiments, the plus isomeric form oftetrabenazine is an alpha isomer.

In certain embodiments, the VMAT2 inhibitor is valbenazine.

In certain embodiments, the daily amount of deutetrabenazine isadministered in one dose or two doses.

In certain embodiments, the daily amount of deutetrabenazine is chosenfrom about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg,about 36 mg, about 42 mg, about 48 mg, about 54 mg, about 60 mg, about66 mg, about 72 mg, and about 78 mg. In certain embodiments, the dailyamount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about 48mg.

In certain embodiments, the daily amount of deutetrabenazine isadministered in two doses, consisting of a first dose and a second dose.

In certain embodiments:

the first dose about 6 mg and the second dose is about 6 mg;

the first dose about 9 mg and the second dose is about 9 mg;

the first dose about 12 mg and the second dose is about 12 mg;

the first dose about 15 mg and the second dose is about 15 mg;

the first dose about 18 mg and the second dose is about 18 mg;

the first dose about 21 mg and the second dose is about 21 mg;

the first dose about 24 mg and the second dose is about 24 mg;

the first dose about 27 mg and the second dose is about 27 mg;

the first dose about 30 mg and the second dose is about 30 mg;

the first dose about 33 mg and the second dose is about 33 mg;

the first dose about 36 mg and the second dose is about 36 mg; and

the first dose about 39 mg and the second dose is about 39 mg.

In certain embodiments:

the first dose about 6 mg and the second dose is about 6 mg;

the first dose about 9 mg and the second dose is about 9 mg;

the first dose about 12 mg and the second dose is about 12 mg;

the first dose about 15 mg and the second dose is about 15 mg;

the first dose about 18 mg and the second dose is about 18 mg;

the first dose about 21 mg and the second dose is about 21 mg; and

the first dose about 24 mg and the second dose is about 24 mg.

In certain embodiments, the daily amount of deutetrabenazine is about 6mg to about 78 mg. In certain embodiments, the daily amount ofdeutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg,about 24 mg, about 30 mg, about 36 mg, about 42 mg, about 48 mg, about54 mg, about 60 mg, about 66 mg, about 72 mg, and about 78 mg. Incertain embodiments, the daily amount of deutetrabenazine is chosen fromabout 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36mg, about 42 mg, and about 48 mg. In certain embodiments, the dailyamount of deutetrabenazine administered is less than or equal to about48 mg, or less than or equal to about 36 mg for subjects concurrentlyreceiving a strong CYP2D6 inhibitor. In certain embodiments, the strongCYP2D6 inhibitor is chosen from fluoxetine, paroxetine, bupropion,quinidine, cinacalcet, and ritonavir. In certain embodiments, the strongCYP2D6 inhibitor is chosen from paroxetine, fluoxetine, and bupropion.

In certain embodiments, the chorea control is improved by a reduction ofat least 0.5 points on the Total Maximal Chorea (TMC) score. In certainembodiments, the reduction in TMC score is at least 1 point. In certainembodiments, the reduction in TMC score is at least 1.5 points. Incertain embodiments, the reduction in TMC score is at least 2.0 points.In certain embodiments, the reduction in TMC score is at least 2.5points. In certain embodiments, the improvement is over a pre-treatment,“baseline” TMC score of at least 8.0. In certain embodiments, theimprovement is over a pre-treatment, “baseline” TMC score of at least10.0. In certain embodiments, the improvement is over a pre-treatment,“baseline” TMC score of at least 12.0. In certain embodiments, theimprovement is over a pre-treatment, “baseline” TMC score of at least12.7. In certain embodiments, the improvement is over a pre-treatment,“baseline” TMC score of at least 14.0.

In certain embodiments, chorea is reduced by at least 10%. In certainembodiments, chorea is reduced by at least 15%. In certain embodiments,chorea is reduced by at least 20%.

In certain embodiments, motor function is improved.

In certain embodiments, motor function is improved by a reduction of atleast 1 point on the Total Motor Score (TMS). In certain embodiments,the reduction in TMS score is at least 2 points. In certain embodiments,the reduction in TMS score is at least 3 points. In certain embodiments,the reduction in TMS score is at least 4 points.

In certain embodiments, dystonia is improved. In certain embodiments,gait is improved. In certain embodiments, postural instability isalleviated. In certain embodiments, treatment reduces the symptoms ofparkinsonism.

In certain embodiments, the treatment does not worsen the subject'sbalance. In certain embodiments, the treatment improves balance.

In certain embodiments, the subject is much improved on the PGIC scale.In certain embodiments, the subject is very much improved on the PGICscale. In certain embodiments, the subject is much improved on the CGICscale. In certain embodiments, the subject is very much improved on theCGIC scale. In certain embodiments, the subject is much improved on thePGIC and CGIC scales. In certain embodiments, the subject is very muchimproved on the PGIC and CGIC scales.

In certain embodiments, the treatment improves physical functioning. Incertain embodiments, the subject's physical functioning is improved asmeasured by the SF-36 physical functioning scale. In certainembodiments, the subject's physical functioning is improved as measuredby the SF-36 physical functioning scale from baseline. In certainembodiments, the subject's physical functioning is improved as measuredby the SF-36 physical functioning scale compared to untreated subjects.

In certain embodiments, the treatment improves swallowing.

In certain embodiments, treatment causes no significant increase ininsomnia, depression, anxiety, agitation, suicidal ideation, akathisia,irritability, or fatigue.

In certain embodiments, treatment causes no significant parkinsonism ordysphagia.

In certain embodiments, the treatment does not significantly prolong theQT interval. In certain embodiments, the treatment does notsignificantly change the QTcF value. In certain embodiments, the maximalincreases in QTcF is less than 5 ms.

Also provided are embodiments wherein any embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive. Also provided is the use ofdeutetrabenazine, or a VMAT2 inhibitor, for improving motor function ina subject with Huntington's disease, tardive dyskinseia, or Tourettesyndrome, as set forth herein or in any of the embodiments above. Alsoprovided is the use of deutetrabenazine, or a VMAT2 inhibitor, in themanufacture of a medicament for improving motor function in a subjectwith Huntington's disease, tardive dyskinseia, or Tourette syndrome, asset forth herein or in any of the embodiments above. Also provided is acomposition comprising deutetrabenazine, or a VMAT2 inhibitor, for usein improving motor function in a subject with Huntington's disease,tardive dyskinseia, or Tourette syndrome, as set forth herein or in anyof the embodiments.

Also provided is a method of reducing motor or phonic tics in a subjectwith Tourette syndrome, comprising the administration of about a dailyamount of deutetrabenazine.

In certain embodiments, the tics are motor tics.

In certain embodiments, the tics are phonic tics.

In certain embodiments, the subject is between 6 and 16 years of age. Incertain embodiments, the subject is between 12 and 18 years of age. Incertain embodiments, the subject is between 6 and 18 years of age.

In certain embodiments, the daily amount of deutetrabenazine is about 6mg to about 48 mg. In certain embodiments, the daily amount ofdeutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg,about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about 48 mg. Incertain embodiments, the daily amount of deutetrabenazine administeredis less than or equal to about 48 mg, or less than or equal to about 36mg for subjects concurrently receiving a strong CYP2D6 inhibitor. Incertain embodiments, the strong CYP2D6 inhibitor is chosen fromfluoxetine, paroxetine, bupropion, quinidine, cinacalcet, and ritonavir.In certain embodiments, the strong CYP2D6 inhibitor is chosen fromparoxetine, fluoxetine, and bupropion.

In certain embodiments, the daily amount of deutetrabenazine isadministered with food.

In certain embodiments, the daily amount of deutetrabenazine is splitinto at least two doses.

In certain embodiments, the daily amount of deutetrabenazine isadministered in two equal doses, consisting of a first dose and a seconddose.

In certain embodiments, the motor or phonic tics are reduced ≥25% asmeasured by the Total Tic Score of the Yale Global Tic Severity Scale.

In certain embodiments, the motor or phonic tics are reduced by 2 ormore points on the Tourette Syndrome Clinical Global Impression(TS-CGI).

In certain embodiments, the motor or phonic tics are reduced by 1 ormore points on the Tourette Syndrome Patient Global Impression ofseverity (TS-PGIS). In certain embodiments, the motor or phonic tics arereduced by 2 or more points on the Tourette Syndrome Patient GlobalImpression of severity (TS-PGIS).

In certain embodiments, the reduction is from baseline to at least twoweeks.

In certain embodiments, the reduction is from baseline to at least fourweeks. In certain embodiments, the reduction is from baseline to atleast eight weeks. In certain embodiments, the reduction is frombaseline to at least twelve weeks.

Also provided are embodiments wherein any embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive. Also provided is the use ofdeutetrabenazine, or a VMAT2 inhibitor, for reducing motor or phonictics in a subject with Tourette syndrome, as set forth herein or in anyof the embodiments above. Also provided is the use of deutetrabenazine,or a VMAT2 inhibitor, in the manufacture of a medicament for reducingmotor or phonic tics in a subject with Tourette syndrome, as set forthherein or in any of the embodiments above. Also provided is acomposition comprising deutetrabenazine, or a VMAT2 inhibitor, for usein reducing motor or phonic tics in a subject with Tourette syndrome, asset forth herein or in any of the embodiments above.

Also provided is a method of reducing motor and phonic tics in a subjectwith Tourette syndrome, comprising the administration of about a dailyamount of deutetrabenazine.

In certain embodiments, the daily amount of deutetrabenazine is about 6mg to about 48 mg. In certain embodiments, the daily amount ofdeutetrabenazine is between 6 and 48 mg. In certain embodiments, thedaily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg,about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, andabout 48 mg. In certain embodiments, the daily amount ofdeutetrabenazine administered is less than or equal to about 48 mg, orless than or equal to about 36 mg for subjects concurrently receiving astrong CYP2D6 inhibitor. In certain embodiments, the strong CYP2D6inhibitor is chosen from fluoxetine, paroxetine, bupropion, quinidine,cinacalcet, and ritonavir. In certain embodiments, the strong CYP2D6inhibitor is chosen from paroxetine, fluoxetine, and bupropion.

In certain embodiments, the daily amount of deutetrabenazine isadministered with food.

In certain embodiments, the daily amount of deutetrabenazine is splitinto at least two doses.

In certain embodiments, the daily amount of deutetrabenazine isadministered in two equal doses, consisting of a first dose and a seconddose.

In certain embodiments, the subject is between 6 and 16 years of age. Incertain embodiments, the subject is between 12 and 18 years of age. Incertain embodiments, the subject is between 6 and 18 years of age.

In certain embodiments, the motor and phonic tics are reduced ≥25% asmeasured by the Total Tic Score of the Yale Global Tic Severity Scale.

In certain embodiments, the motor or phonic tics are reduced by 2 ormore points on the Tourette Syndrome Clinical Global Impression.

In certain embodiments, the reduction is from baseline to at least twoweeks. In certain embodiments, the reduction is from baseline to atleast four weeks. In certain embodiments, the reduction is from baselineto at least eight weeks. In certain embodiments, the reduction is frombaseline to at least twelve weeks.

In certain embodiments, the deutetrabenazine is a plus isomeric form ofdeutetrabenazine. In certain embodiments, the plus isomeric form ofdeutetrabenazine is an alpha isomer.

In certain embodiments, the treatment does not significantly prolong theQT interval. In certain embodiments, the treatment does notsignificantly change the QTcF value. In certain embodiments, the maximalincreases in QTcF is less than 5 ms.

Also provided are embodiments wherein any embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive. Also provided is the use ofdeutetrabenazine, or a VMAT2 inhibitor, for reducing motor and phonictics in a subject with Tourette syndrome, as set forth herein or in anyof the embodiments above. Also provided is the use of deutetrabenazine,or a VMAT2 inhibitor, in the manufacture of a medicament for reducingmotor and phonic tics in a subject with Tourette syndrome, as set forthherein or in any of the embodiments above. Also provided is acomposition comprising deutetrabenazine, or a VMAT2 inhibitor, for usein reducing motor and phonic tics in a subject with Tourette syndrome,as set forth herein or in any of the embodiments above.

Also provided is a method of reducing tic severity as measured by thesubject's Tourette Syndrome Patient Global Impression of Severity(TS-PGIS) in a subject with Tourette syndrome, comprising theadministration of about a daily amount of deutetrabenazine. In certainembodiments, the method comprises: a) administering a daily amount ofdeutetrabenazine; and b) at least once every 4 weeks, assessing ticseverity using the TS-PGIS. In further embodiments, the methodadditionally comprises: c) after assessing tic severity using theTS-PGIS, if the daily amount of deutetrabenazine is tolerable,increasing the daily amount of deutetrabenazine by at least 6 mg/day; d)repeating steps b) and c) until TS-PGIS is not further reduced or thedaily amount of the deutetrabenazine is tolerated; and e) if anysubsequent amount is not tolerated, decreasing the daily amount ofdeutetrabenazine downward by 6 mg/day.

In certain embodiments, the tics are motor tics.

In certain embodiments, the tics are phonic tics.

In certain embodiments, the subject is between 6 and 16 years of age. Incertain embodiments, the subject is between 12 and 18 years of age. Incertain embodiments, the subject is between 6 and 18 years of age.

In certain embodiments, the daily amount of deutetrabenazine is between6 and 48 mg. In certain embodiments, the daily amount ofdeutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg,about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about 48 mg. Incertain embodiments, the daily amount of deutetrabenazine isadministered with food.

In certain embodiments, tic severity is assessed using the TS-PGIS atleast every two weeks. In certain embodiments, tic severity is assessedusing the TS-PGIS at least weekly. In certain embodiments, tic severityis assessed using the TS-PGIS at least monthly. In certain embodiments,tic severity is assessed using the TS-PGIS at least every three months.

In certain embodiments, the daily amount of deutetrabenazine is splitinto two doses.

In certain embodiments, the reduction is from baseline to at least twoweeks. In certain embodiments, the reduction is from baseline to atleast four weeks. In certain embodiments, the reduction is from baselineto at least eight weeks. In certain embodiments, the reduction is frombaseline to at least twelve weeks.

In certain embodiments, the deutetrabenazine is a plus isomeric form ofdeutetrabenazine. In certain embodiments, the plus isomeric form ofdeutetrabenazine is an alpha isomer.

In certain embodiments, the treatment does not significantly prolong theQT interval. In certain embodiments, the treatment does notsignificantly change the QTcF value. In certain embodiments, the maximalincreases in QTcF is less than 5 ms.

Also provided are embodiments wherein any embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive. Also provided is the use ofdeutetrabenazine for reducing tic severity as measured by the subject'sTourette Syndrome Patient Global Impression of Severity (TS-PGIS), asset forth herein or in any of the embodiments above. Also provided isthe use of deutetrabenazine in the manufacture for reducing tic severityas measured by the subject's Tourette Syndrome Patient Global Impressionof Severity (TS-PGIS), as set forth herein or in any of the embodimentsabove. Also provided is a composition comprising deutetrabenazine foruse in reducing tic severity as measured by the subject's TouretteSyndrome Patient Global Impression of Severity (TS-PGIS), as set forthherein or in any of the embodiments above.

Also provided is a method of maintaining control of abnormal involuntarymovements in a human subject with a movement disorder, comprisingadministering to the subject a therapeutically effective daily amount ofdeutetrabenazine for a period of time sufficient to do one or more ofthe following: reduce chorea by at least 10%; improve motor function byat least 10%; improve physical functioning; improve swallowing; improvebalance; reduce abnormal involuntary movements in subjects with tardivedyskinesia; reduce motor tics; reduce vocal/phonic tics; reduce motorand vocal/phonic tics; reduce impairment in subjects with Tourettesyndrome; reduce the severity of Tourette syndrome; reduce the patientglobal impression of severity in subjects with Tourette Syndrome; andmuch or very much improve the subject's patient of clinical globalimpression of change.

In certain embodiments, the disorder is chosen from Huntington'sdisease, tardive dyskinesia, and Tourette syndrome.

In certain embodiments, or improvement in each of the endpoints above ismeasured as follows: reduction in chorea is measured by the UnifiedHuntington's Disease Rating Scale (UHDRS) or a subscale thereof;reduction in chorea is measured by the Total Maximal Chorea (TMC) scoreof the UHDRS; improvement in motor function is measured by the TotalMotor Score (TMS) score of the UHDRS; improvement in physicalfunctioning is measured by the SF-36 physical functioning scale;improvement in swallowing is measured by the Swallowing DisturbanceQuestionnaire (SDQ); improvement in balance is measured by the BergBalance Test (BBT); reduction in abnormal involuntary movements insubjects with tardive dyskinesia is measured by the AIMS; reduction inmotor tics in subjects with Tourette Syndrome is measured by the MTSS ofthe YGTSS; reduction in vocal/phonic tics in subjects with TouretteSyndrome is measured by the VTSS of the YGTSS; reduction in total (motorand vocal/phonic) tics is measured by the TTS of the YGTSS; reduction inimpairment is measured by the Impairment score of the YGTSS; reductionin the severity of Tourette syndrome is measured by the the globalseverity score of the YGTSS; and reduction in patient global impressionof severity in subjects with Tourette Syndrome is measured by theTS-PGIS.

In certain embodiments, the daily amount of deutetrabenazine is about 6mg to about 78 mg. In certain embodiments, the daily amount ofdeutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg,about 24 mg, about 30 mg, about 36 mg, about 42 mg, about 48 mg, about54 mg, about 60 mg, about 66 mg, about 72 mg, and about 78 mg. Incertain embodiments, the daily amount of deutetrabenazine is chosen fromabout 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36mg, about 42 mg, and about 48 mg. In certain embodiments, the dailyamount of deutetrabenazine administered is less than or equal to about48 mg, or less than or equal to about 36 mg for subjects concurrentlyreceiving a strong CYP2D6 inhibitor. In certain embodiments, the strongCYP2D6 inhibitor is chosen from fluoxetine, paroxetine, bupropion,quinidine, cinacalcet, and ritonavir. In certain embodiments, the strongCYP2D6 inhibitor is chosen from paroxetine, fluoxetine, and bupropion.

In certain embodiments, the sufficient period of time is at least fourweeks. In certain embodiments, the sufficient period of time is at leasteight weeks. In certain embodiments, the sufficient period of time is atleast twelve weeks.

In certain embodiments, the reduction or improvement in the relevantmeasure or measures is by at least 10% over baseline. In certainembodiments, the reduction or improvement in the relevant measure or atleast one of the measures is by at least 20% over baseline. In certainembodiments, the reduction or improvement in the relevant measure or atleast one of the measures is by at least 30% over baseline. In certainembodiments, the reduction or improvement in the relevant measure or atleast one of the measures is by at least 40% over baseline. In certainembodiments, the reduction or improvement in the relevant measure or atleast one of the measures is by at least 50% over baseline.

In certain embodiments, the disorder is Huntington's disease. In certainembodiments, the abnormal involuntary movement is chorea associated withHuntington's disease.

In certain embodiments, the disorder is tardive dyskinesia.

In certain embodiments, the disorder is Tourette syndrome. In certainembodiments, the abnormal involuntary movement is a tic associated withTourette syndrome.

In certain embodiments, the deutetrabenazine is a plus isomeric form ofdeutetrabenazine. In certain embodiments, the plus isomeric form ofdeutetrabenazine is an alpha isomer.

In certain embodiments, the treatment does not significantly prolong theQT interval. In certain embodiments, the treatment does notsignificantly change the QTcF value. In certain embodiments, the maximalincreases in QTcF is less than 5 ms.

Also provided are embodiments wherein any embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive. Also provided is the use ofdeutetrabenazine for maintaining control of abnormal involuntarymovements in a human subject with a movement disorder, as set forthherein or in any of the embodiments above. Also provided is the use ofdeutetrabenazine in the manufacture of a medicament for maintainingcontrol of abnormal involuntary movements in a human subject with amovement disorder, as set forth herein or in any of the embodimentsabove. Also provided is a composition comprising deutetrabenazine formaintaining control of abnormal involuntary movements in a human subjectwith a movement disorder, as set forth herein or in any of theembodiments above.

Compositions

Tetrabenazine (Nitoman, Xenazine, Ro 1-9569),1,3,4,6,7,11b-Hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinoline,is a vesicular monoamine transporter 2 (VMAT2) inhibitor. Tetrabenazineis commonly prescribed for the treatment of Huntington's disease (Savaniet al., Neurology 2007, 68(10), 797; and Kenney et al., Expert Review ofNeurotherapeutics 2006, 6(1), 7-17). Tetrabenazine is subject toextensive oxidative metabolism, including 0-demethylation of the methoxygroups, as well as hydroxylation of the isobutyl group (Schwartz et al.,Biochem. Pharmacol., 1966, 15, 645-655). Adverse effects associated withthe administration of tetrabenazine include neuroleptic malignantsyndrome, drowsiness, fatigue, nervousness, anxiety, insomnia,agitation, confusion, orthostatic hypotension, nausea, dizziness,depression, and Parkinsonism.

Deuterium Enriched Tetrabenazine Analogues

d6-Tetrabenazine (equivalently, deutetrabenazine, SD-809, or DTBZ) is adeuterated analog of tetrabenazine currently under clinical development.U.S. Pat. No. 8,524,733, US 20100130480, and US 20120003330.

d6-Tetrabenazine (RR,SS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d₃)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one

In all of the methods and compositions disclosed herein usingdeutetrabenazine, the deutetrabenazine may be administered or formulatedas part of a pharmaceutical composition wherein the composition hasdeuterium enrichment of at least 90% at each of the positions designatedD. In certain embodiments, the composition has deuterium enrichment ofat least 95% at each of the positions designated D. In certainembodiments, the composition has deuterium enrichment of at least 98% ateach of the positions designated D.

In humans, as shown below, d₆-tetrabenazine is rapidly and extensivelyconverted in the liver (similarly to non-isotopically enrichedtetrabenazine) to major, active dihydrotetrabenazine (HTBZ) metabolitesreferred to as d₆-α-HTBZ and d₆-β-HTBZ (as a mixture of the + and −isomers) which have the structures below (+ isomers shown). Thesemetabolites are believed to drive clinical efficacy.

Deuterium substituted tetrabenazines include, in addition todeutetrabenazine disclosed above, compounds as disclosed in U.S. Pat.No. 8,524,733, US 20100130480, and US 20120003330, andPCT/US2014/066740, filed Nov. 14, 2014. Examples of such compounds aregiven in the following structural formulas.

In certain embodiments of the present invention, compounds havestructural Formula

-   -   or a salt, solvate, or prodrug thereof, wherein:    -   R₁-R₂₇ are independently selected from the group consisting of        hydrogen and deuterium; and    -   at least one of R₁-R₂₇ is deuterium.

In certain embodiments, Formula I can include a single enantiomer, amixture of the (+)-enantiomer and the (−)-enantiomer, a mixture of about90% or more by weight of the (−)-enantiomer and about 10% or less byweight of the (+)-enantiomer, a mixture of about 90% or more by weightof the (+)-enantiomer and about 10% or less by weight of the(−)-enantiomer, an individual diastereomer, or a mixture ofdiastereomers thereof.

In certain embodiments of the present invention, compounds havestructural Formula II:

-   -   or a salt thereof, wherein:    -   R₂₈-R₄₆ and R₄₈-R₅₆ are independently selected from the group        consisting of hydrogen and deuterium;    -   R₄₇ is selected from the group consisting of hydrogen,        deuterium, —C(O)O-alkyl and —C(O)—C₁₋₆alkyl, or a group        cleavable under physiological conditions, wherein said alkyl or        C₁₋₆alkyl is optionally substituted with one or more        substituents selected from the group consisting of —NH—C(NH)NH₂,        —CO₂H, —CO₂alkyl, —SH, —C(O)NH₂, —NH₂, phenyl, —OH,        4-hydroxyphenyl, imidazolyl, and indolyl, and any R₄₆        substituent is further optionally substituted with deuterium;        and    -   at least one of R₂₈-R₅₆ is deuterium or contains deuterium.

In certain embodiments, the compounds of Formula II have alphastereochemistry.

In further embodiments, the compounds of Formula II have betastereochemistry.

In yet further embodiments, the compounds of Formula II are a mixture ofalpha and beta stereoisomers. In yet further embodiments, the ratio ofalpha/beta stereoisomers is at least 100:1, at least 50:1, at least20:1, at least 10:1, at least 5:1, at least 4:1, at least 3:1, or atleast 2:1. In yet further embodiments, the ratio of beta/alphastereoisomers is at least 100:1, at least 50:1, at least 20:1, at least10:1, at least 5:1, at least 4:1, at least 3:1, or at least 2:1.

In certain embodiments, if R₅₀-R₅₆ are deuterium, at least one of R₁-R₄₉is deuterium.

In certain embodiments of the present invention, compounds havestructural Formula III:

-   -   or a salt, stereoisomer, or racemic mixture thereof, wherein:    -   R₅₇-R₈₃ are independently selected from the group consisting of        hydrogen and deuterium; and    -   at least one of R₅₇-R₈₃ is deuterium.

In certain embodiments of the present invention, compounds havestructural Formula IV:

-   -   or a salt, diastereomer, or mixture of diastereomers thereof,        wherein:    -   R₈₄-R₁₁₀ are independently selected from the group consisting of        hydrogen and deuterium; and    -   at least one of R₈₄-R₁₁₀ is deuterium.

Deuterium substituted tetrabenazine metabolites include, in addition tod₆-α-HTBZ and d₆-β-HTBZ disclosed above, compounds disclosed in of thefollowing structural formulas.

The terms “alpha-dihydrotetrabenazine”, “α-dihydrotetrabenazine”, or theterms “alpha” or “alpha stereoisomer” or the symbol “α” as applied todihydrotetrabenazine refers to either of the dihydrotetrabenazinestereoisomers having the structural formulas shown below, or a mixturethereof:

The terms “alpha” or “alpha stereoisomer” or the symbol “a” as appliedto a compound of Formula II refers to either of the stereoisomers ofcompounds of Formula II shown below, or a mixture thereof:

The terms “beta-dihydrotetrabenazine”, “β-dihydrotetrabenazine”, or theterms “beta” or “beta stereoisomer” or the symbol “β” as applied todihydrotetrabenazine refers to either of the dihydrotetrabenazinestereoisomers having the structural formulas shown below, or a mixturethereof:

The terms “beta” or “beta stereoisomer” or the symbol “β” as applied toa compound of Formula II refers to either of the stereoisomers ofcompounds of Formula II shown below, or a mixture thereof:

The terms “3S,11bS enantiomer” or the term “3R,11bR enantiomer” refersto either of the d₆-tetrabenazine M4 metabolite stereoisomers having thestructural formulas shown below:

In certain embodiments, a chemical structure may be drawn as either the3S,11bS enantiomer or the 3R,11bR enantiomer, but the text of thespecification may indicate that the 3S,11bS enantiomer, the 3R,11bRenantiomer, a racemic mixture thereof, or all of the foregoing may beintended to be described.

The terms “(3S, 11bS)-enantiomer” or “(3R, 11bR)-enantiomer” or the asapplied to a compound of Formula I refers to either of the stereoisomersof compounds of Formula III shown below:

The term “mixture of diastereomers” refers to either of thed₆-tetrabenazine M1 metabolite stereoisomers having the structuralformulas shown below:

In certain embodiments, a chemical structure may be drawn as one of thediastereomers shown above, but the text of the specification mayindicate that each individual diastereomer or a mixture thereof, or allof the foregoing may be intended to be described.

The term “mixture of diastereomers” as applied to a compound of FormulaIV refers to a mixture of the stereoisomers of compounds of Formula IVshown below:

Additional deuterium enriched tetrabenazine analogues include analogs ofvalbenazine. Valbenazine (NBI-98854, CAS #1025504-59-9,(S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl2-amino-3-methylbutanoate) is a VMAT2 inhibitor. Valbenazine iscurrently under investigation for the treatment of movement disordersincluding tardive dyskinesia. WO 2008058261; WO 2011153157; and U.S.Pat. No. 8,039,627. Valbenazine, a valine ester of(+)-α-dihydrotetrabenazine, in humans is slowly hydrolyzed to(+)-α-dihydrotetrabenazine which is an active metabolite oftetrabenazine which is currently used for the treatment of Huntington'sdisease. Savani et al., Neurology 2007, 68(10), 797; and Kenney et al.,Expert Review of Neurotherapeutics 2006, 6(1), 7-17.

Dihydrotetrabenazine, formed by hydrolysis of the valine ester ofvalbenazine, is subject to extensive oxidative metabolism, including0-demethylation of the methoxy groups, as well as hydroxylation of theisobutyl group (Schwartz et al., Biochem. Pharmacol., 1966, 15,645-655). Adverse effects associated potentially associated with theadministration of valbenazine include neuroleptic malignant syndrome,drowsiness, fatigue, nervousness, anxiety, insomnia, agitation,confusion, orthostatic hypotension, nausea, dizziness, depression, andParkinsonism.

Deuterium-substituted analogues of valbenazine include those asdisclosed in WO2014120654. Examples of such compounds are given in theFormulas below.

In certain embodiments of the present invention, compounds havestructural Formula

or a salt thereof, wherein:

R₁-R₁₉ and R₂₁-R₂₉ are independently selected from the group consistingof hydrogen and deuterium;

R₂₀ is selected from the group consisting of hydrogen, deuterium,—C(O)O-alkyl and —C(O)—C₁₋₆alkyl, or a group cleavable underphysiological conditions, wherein said alkyl or C₁₋₆alkyl is optionallysubstituted with one or more substituents selected from the groupconsisting of —NH—C(NH)NH₂, —CO₂H, —CO₂alkyl, —SH, —C(O)NH₂, —NH₂,phenyl, —OH, 4-hydroxyphenyl, imidazolyl, and indolyl, and any R₂₀substituent is further optionally substituted with deuterium; and

at least one of R₁-R₂₉ is deuterium or contains deuterium.

In certain embodiments, the compounds of Formula V have (+)-alphastereochemistry.

In certain embodiments, the compounds of Formula V have (−)-alphastereochemistry.

In further embodiments, the compounds of Formula V have (+)-betastereochemistry.

In further embodiments, the compounds of Formula V have (−)-betastereochemistry.

In yet further embodiments, the compounds of Formula I are a mixture ofalpha and beta stereoisomers. In yet further embodiments, the ratio ofalpha/beta stereoisomers is at least 100:1, at least 50:1, at least20:1, at least 10:1, at least 5:1, at least 4:1, at least 3:1, or atleast 2:1. In yet further embodiments, the ratio of beta/alphastereoisomers is at least 100:1, at least 50:1, at least 20:1, at least10:1, at least 5:1, at least 4:1, at least 3:1, or at least 2:1.

In certain embodiments, disclosed herein is a compound of structuralFormula VI:

or a salt or stereoisomer thereof, wherein:

R₁-R₁₉ and R₂₁-R₃₉ are independently selected from the group consistingof hydrogen and deuterium;

at least one of R₁-R₁₉ and R₂₁-R₃₉ is deuterium.

In certain embodiments of the present invention, compounds havestructural Formula VII:

or a salt or stereoisomer thereof, wherein:

R₂₀ is selected from the group consisting of —C(O)O-alkyl and—C(O)—C₁₋₆alkyl, or a group cleavable under physiological conditions,wherein said alkyl or C₁₋₆alkyl is optionally substituted with one ormore substituents selected from the group consisting of —NH—C(NH)NH₂,—CO₂H, —CO₂alkyl, —SH, —C(O)NH₂, —NH₂, phenyl, —OH, 4-hydroxyphenyl,imidazolyl, and indolyl, and any R₂₀ substituent is further optionallysubstituted with deuterium.

The compounds as disclosed herein may also contain less prevalentisotopes for other elements, including, but not limited to, ¹³C or ¹⁴Cfor carbon, ³³S, ³⁴S, or ³⁶S for sulfur, ¹⁵N for nitrogen, and ¹⁷O or¹⁸O for oxygen.

Deuterium Kinetic Isotope Effect

Deuterium (D) is a naturally occurring, non-radioactive, stable isotopeof hydrogen (H), that contains both a proton and a neutron in itsnucleus. The presence of the neutron doubles the mass of D when comparedto H, which in turn increases the vibrational frequency of the C-Dcovalent bond as compared to the C—H covalent bond. An increase in thevibrational frequency of a covalent bond results in an increase in theactivation energy required to break that bond, and consequentially anincrease in the bond strength. This increased covalent bond strength canin certain instances alter the kinetics of the covalent bond cleavageresulting in what is known as the Kinetic Isotope Effect (KIE). Undercertain specific conditions that involve various quantum mechanicalaspects of the covalent bond cleavage, the replacement of a covalent C—Hbond with a covalent C-D bond can result in a meaningful deuterium KIE.A large deuterium KIE for a drug that is a CYP450 substrate can incertain instances lead to an improvement in the pharmacokineticparameters of that drug, which can potentially result in adifferentiation between the deuterated and the non-deuterated drugs. Thecovalent C-D bonds in deutetrabenazine satisfy a number of chemical andbiological criteria which work in concert to provide a deuterium KIEthat is large enough to slow down the O-demethylation of the activemetabolites of deutetrabenazine as compared to tetrabenazine. It isimportant to note that the magnitude of this deuterium KIE could nothave been predicted a priori, and hence it was not possible to knowahead of time if the replacement of a C—H covalent bond in tetrabenazinewith a C-D covalent bond would have led to a noticeable and/or improvedbiological difference.

Deutetrabenazine or d₆-tetrabenazine is a VMAT2 inhibitor.

In the d₆-tetrabenazine, six hydrogen atoms are replaced with deuteriumatoms as shown in foregoing figure. There is substantial evidence thatd₆-tetrabenazine forms stable covalent bonds, and that itstrideuteromethyl group (—CD₃) is a covalently bound stable moiety withno distinctions or qualifications of that bond as compared to a methylgroup (—CH₃).

First, the covalent nature of the C-D bond can be established byspectroscopic methods such as Infrared (IR) Spectroscopy. Thecharacteristic IR absorption of C-D stretches at approximately 2000-2300cm-1 (Miller and Corcelli, 2009) is often used by researchers assite-specific and non-perturbative probes for protein studies (Millerand Corcelli, 2009; Zimmermann et al., 2011). d₆-tetrabenazine hasdistinct IR absorptions at 2060-2250 cm-1 which are attributed to theC-D stretches. These absorption bands are absent from the IR spectrum ofthe non-deuterated form of tetrabenazine.

Second, d₆-tetrabenazine is not a salt form of tetrabenazine. The massspectrum of deutetrabenazine displays the protonated molecular ion atm/z 324.18 [M+1]. This agrees with the predicted mass number ofd₆-tetrabenazine as an intact molecule.

Third, deuterium atoms in d₆-tetrabenazine do not exchange with hydrogenunder normal physiological conditions. The pKa of non-conjugatedaliphatic C—H bonds is in the range of 45-50, which means that atequilibrium, the ratio of dissociated to non-dissociated species is lessthan 10-45. By comparison, the C—H bonds of the methoxy groups oftetrabenazine, and by extension, the C-D bonds of the methoxy groups ofd₆-tetrabenazine are even less acidic, with a pKa value approaching 50.This means that one would need to increase the pH of an aqueous solutionto more than 45 before any of the deuterium atoms in deutetrabenazinecan potentially start exchanging with hydrogen atoms.

Finally, d₆-tetrabenazine or deutetrabenazine has been administered tohumans in clinical studies, and subject to various in vitro incubationswith multiple enzymatic processes. The known active metabolites as wellas further downstream metabolites have been monitored in vitro incubatesand/or in human plasma by LC/MS/MS methods. These metabolites have beensynthesized and confirmed to contain the expected trideuteromethylgroups (—CD₃), confirming that the covalent C-D bonds indeutetrabenazine are stable and carried into the downstream metabolitesof deutetrabenazine. Deutetrabenazine has a differentiatedpharmacokinetics profile compared to d₀-tetrabenazine.

Due to the deuterium kinetic isotope effect (KIE), replacing H with a Din a covalent C-H bond in a small molecule drug has the potential toattenuate the metabolism of the drug (Baillie, 1981) by requiring moreenergy for cleavage by enzymes such as cytochrome P450 isozymes(CYP450). The magnitude of the deuterium KIE varies depending on thenature of the C-H bond that is being broken and whether the cleavage ofthat bond is the rate-limiting step in the oxidative metabolism of thedrug by a CYP isozyme.

By attenuating metabolism in this manner, elimination half-life(t_(1/2)), exposure (AUC [area under the plasma level-time curve]), andpeak plasma concentration (Cmax) may be altered relative to thenon-deuterated form of the drug (Kushner et al., 1999; Baillie, 1981).The substitution of D for H at specific positions in a drug has also thepotential to attenuate the breakdown of the deuterium containingmetabolites of the deuterated parent drug. Many deuterium substitutionsof key oxidative metabolic sites do not produce any effects; thusempirical data are required to determine whether deuteration haspotentially relevant outcomes in vivo. Tetrabenazine contains numerousC—H covalent bonds that are subject to oxidative metabolism by CYP450enzymes. For all of the foregoing reasons, a medicine with a longerhalf-life may result in greater efficacy, better safety andtolerability, improved quality of life and potential for cost savings inthe long term. Various deuteration patterns can be used to (a) reduce oreliminate unwanted metabolites, (b) increase the half-life of the parentdrug, (c) decrease the number of doses needed to achieve a desiredeffect, (d) decrease the amount of a dose needed to achieve a desiredeffect, (e) increase the formation of active metabolites, if any areformed, (f) decrease the production of deleterious metabolites inspecific tissues, and/or (g) create a more effective drug and/or a saferdrug for polypharmacy, whether the polypharmacy be intentional or not.The deuteration approach has demonstrated the ability to slow themetabolism of tetrabenazine and attenuate interpatient variability.

Abbreviations and Definitions

To facilitate understanding of the disclosure, a number of terms andabbreviations as used herein are defined below as follows:

All publications and references cited herein are expressly incorporatedherein by reference in their entirety. However, with respect to anysimilar or identical terms found in both the incorporated publicationsor references and those explicitly put forth or defined in thisdocument, then those terms definitions or meanings explicitly put forthin this document shall control in all respects.

The singular forms “a,” “an,” and “the” may refer to plural articlesunless specifically stated otherwise.

When ranges of values are disclosed, and the notation “from n1 . . . ton2” or “n1-n2” is used, where n1 and n2 are the numbers, then unlessotherwise specified, this notation is intended to include the numbersthemselves and the range between them. This range may be integral orcontinuous between and including the end values.

The term “and/or” when used in a list of two or more items, means thatany one of the listed items can be employed by itself or in combinationwith any one or more of the listed items. For example, the expression “Aand/or B” is intended to mean either or both of A and B, i.e. A alone, Balone or A and B in combination. The expression “A, B and/or C” isintended to mean A alone, B alone, C alone, A and B in combination, Aand C in combination, B and C in combination or A, B, and C incombination.

The term “about,” as used herein when referring to a measurable valuesuch as an amount of a compound, dose, time, temperature, and the like,is meant to encompass variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1%of the specified amount.

As used herein, the term “abnormal” refers to an activity or featurethat differs from a normal activity or feature.

As used herein, the term “abnormal muscular activity” refers to muscularactivity that differs from the muscular activity in a healthy subject.The abnormal activity may be decreased or increased in comparison tonormal activity. An increase in muscular activity can result inexcessive abnormal movements, excessive normal movements, or acombination of both.

The term “adverse event” (“AE”) means any untoward medical occurrence ina patient administered a drug, regardless of whether it has a causalrelationship with this treatment. An adverse event can, therefore, beany unfavorable and unintended physical sign, symptom, or laboratoryparameter that develops or worsens in severity during the course of thisstudy, or significant worsening of the disease under study or of anyconcurrent disease, whether or not considered related to the study drug.A new condition or the worsening of a pre-existing condition will beconsidered an adverse event. Stable chronic conditions (such asarthritis) that are present before study entry and do not worsen duringthis study will not be considered adverse events. A mild AE is one whichdoes not limit the subject's activities; a moderate AE is one whichcauses some limitation of usual activities; and a severe AE is one whichrenders a subject unable to carry out usual activities.

A “treatment-related adverse event” is an adverse event which, in aphysician's or clinician's judgment, is related to the drugadministered. Such a determination should be understood to often notreduce to a yes/no question, but may lie on a continuum wherein it ismore or less likely that the AE is treatment-related, including thecloseness of manifestation of the event to dosing, the disappearance ofthe AE upon discontinuation or reduction in dose of the drug, and thefailure of other factors (e.g., preexisting conditions, environmentalfactors, etc.) to explain the AE.

The term “CYP2D6 inhibitor” refers to a drug which is inhibits CYP2D6,therefore making it unavailable to metabolize other substrate compounds;co-administration of a drug metabolized by CYP2D6 with a CYP2D6inhibitor should be carried out with caution and often at a reduceddosage, as the plasma concentration of the drug will often be CYP2D6inhibitors include amiodarone, celecoxib, chloroquine, chlorpromazine,cimetidine, citalopram, clomipramine, codeine, deiavirdine, desipramine,dextroprpoxyphene, diltiazem, doxorubicin, entacapone (high dose),fluoxetine, fluphenazine, fluvaxamine, haloperidol, labetalol, lobeline,lomustine, methadone, mibefradil, moclobemide, nortuloxeline,paroxetine, perphenazine, propafenone, quinacrine, quinidine,ranitidine, risperidone, ritonavir, serindole, sertraline, thioridazine,valproic acid, venlafaxine, vinblastine, vincristine, vinorelbine, andyohimbine. Strong CYP2D6 inhibitors include fluoxetine, aroxetine,bupropion, quinidine, cinacalcet, and ritonavir.

The term “degree” as used herein in reference to control of abnormalmuscular activity or abnormal involuntary movement (e.g., chorea) ismeant to be synonymous with “level.”

The term “disorder” as used herein is intended to be generallysynonymous, and is used interchangeably with, the terms “disease”,“syndrome”, and “condition” (as in medical condition), in that allreflect an abnormal condition of the human or animal body or of one ofits parts that impairs normal functioning, is typically manifested bydistinguishing signs and symptoms.

The terms “treat,” “treating,” and “treatment” are meant to includealleviating or abrogating a disorder or one or more of the symptomsassociated with a disorder; or alleviating or eradicating the cause(s)of the disorder itself. As used herein, reference to “treatment” of adisorder is intended to include prevention.

The terms “prevent,” “preventing,” and “prevention” refer to a method ofdelaying or precluding the onset of a disorder; and/or its attendantsymptoms, barring a subject from acquiring a disorder or reducing asubject's risk of acquiring a disorder.

The terms “tolerable” and “tolerability” refer to that amount ofdeuterium-substituted tetrabenazine (e.g., deutetrabenazine) or otherdrug (e.g., deuterium-substituted VMAT inhibitor, or valbenazine) whichproduces low rates of adverse events such as somnolence, irritability,fatigue, vomiting and nausea in patients and where the adverse events donot lead to dose reduction of the deuterium substituted tetrabenazine orother drug, suspension of the deuterium substituted tetrabenazine orother drug, or withdrawal of the drug deuterium substitutedtetrabenazine or other drug. The deuterium substituted tetrabenazine isalso considered tolerable if any underlying symptoms such as depression,anxiety, suicidality, parkinsonism in patients having diseases orconditions, such as Huntington's disease, tardive dyskinesia or Tourettesyndrome, are not worsened. Tolerable and tolerability shall also referto that amount of deutetrabenazine (or other drug, if applicable) whichdoes not necessitate a downward adjustment in regular (e.g., daily)dose, or a suspension of dose, for example due to adverse effects. Atolerable amount may vary from between subjects, and also within asubject over the course of a disease or course of treatment.

The term “adequate” as used herein in reference to control of abnormalmuscular activity or abnormal involuntary movement (e.g., chorea) in asubject refers a level of control which is observable and satisfactoryto the subject. The clinician, investigator, in consultation with thesubject, will determine when an adequate level of control of abnormalmuscular activity or abnormal involuntary movement (e.g., chorea) hasbeen achieved. Typically, the adequacy of a level of control of abnormalmuscular activity or abnormal involuntary movement provided by an amountof a drug will be affected by the tolerability of that amount, and willoften be the maximum tolerated amount which yields an observableincrease in control (the “optimal” amount). The amount ofdeutetrabenazine may be increased on a weekly basis until there isadequate control of chorea, the subject experiences a protocol defined“clinically significant” adverse event (defined as related to studymedication and either a) moderate or severe in intensity or b) meets thecriteria for a Serious Adverse Event (SAE), or the maximal allowabledose is reached. An adequate level may vary from between subjects, andalso within a subject over the course of a disease or course oftreatment.

The phrases “improve,” “improved by,” “reduce,” “reduced by,” and thelike, used in reference to a level, degree, or amount by which somequality is reduced, improved, etc. in a subject or subjects by treatmentwith a compound, is meant to be in comparison to an untreated subject orsubjects. Alternatively, if explicitly so stated, these phrases may bein comparison to a subject or subjects treated with a standard of care.Such measures may be made by reference to a relevant scale or assessmentknown in the art (see, e.g., examples provided herein ofdisorder-control and/or disorder-eradication endpoint scales, and Likertscales).

The term “abnormal involuntary movement,” as used herein, includesinvoluntary movements associated with or caused by movement disorders.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human, monkey, chimpanzee, gorilla, and the like),rodents (e.g., rats, mice, gerbils, hamsters, ferrets, and the like),lagomorphs, swine (e.g., pig, miniature pig), equine, canine, feline,and the like. The terms “subject” and “patient” are used interchangeablyherein in reference, for example, to a mammalian subject, such as ahuman patient.

The GTS-QOL consists of two parts. The first part is typically atwenty-seven question assessment of various aspects of how tics affectthe subject's life, each to be rated on a five-choice scale of noproblem, slight problem, moderate problem, marked problem, or severeproblem. Subscales combining some of these aspects can be focused upon,such as, e.g., the physical/activities of daily living (ADL) subscale.The second part is a simple rating of the subject's life satisfaction,where 100 is extremely satisfied and 0 is extremely dissatisfied.

SF-36 Physical Functioning Score. The SF-36 is a short-form healthsurvey with 36 questions used to evaluate health-related quality of life(Ware, 1996). The SF-36 has been useful in comparing specificpopulations and comparing the relative burden of various diseases. TheSF-36 has been evaluated in HD patients and shown to have robustconstruct validity and test-retest reliability and was also able todiscriminate from age-matched controls and normative data on the 10-itemphysical functioning scale (Ho, 2004). While the entire SF-36 wasadministered in this study, the physical functioning scale (also knownas the PF-10) was analyzed as a key secondary endpoint. The physicalfunctioning scale is a 10-item subset of the SF-36 which examines asubject's perceived health-related limitations with physical activities.The SF-36 physical functioning score is a 10-item scale where subjectsrate their ability to perform routine physical activities such aswalking, climbing stairs, bathing, or dressing. Given the potential forchorea to interfere with basic motor skills, gait, and walking it is notunexpected that subjects with more impaired function would experiencegreater benefit on this measure.

The Tourette Syndrome Patient Global Impression of Severity (TS-PGIS) isa novel five-point scale in which 1 indicates no tics, 2 indicates mildtics (not distressing, noticeable, or interfering with daily life), 3indicates moderate (can be distressing, noticeable, and sometimesinterfering with daily life), 4 indicates marked (very distressing,noticeable, and interfering with daily life), and 5 indicates severe(severely distressing, always noticeable, and preventing of most dailyactivities).

The Tic-Free Interval is a five-point scale in which 1 indicates aninterval of at least one day since the last tic, 2 indicates an intervalof between 6 hours to less than one day since the last tic, 3 indicatesan interval of between one hour and less than 6 hours since the lasttic, 4 indicates an interval of between five minutes to less than onehour since the last tic, and 5 indicates less than five minutes sincethe last tic.

The TS-CGI is a seven-point scale scored by the clinician, in which 1indicates normal or no tics, 2 indicates tics may or may not be present,3 indicates mild, observable motor and/or phonic tics that may or maynot be noticed, would not call attention to the individual, and areassociated with no distress or impairment, 4 indicates moderate,observable motor and/or phonic tics that would always be noticed, wouldcall attention to the individual, and may be associated with somedistress or impairment, 5 indicates marked, exaggerated motor and/orphonic tics that are disruptive, would always call attention to theindividual, and are always associated with significant distress orimpairment, 6 indicates severe, extremely exaggerated motor and/orphonic tics that are disruptive, would always call attention to theindividual, and are associated with injury or inability to carry outdaily functions, and 7 indicates extreme, incapacitating tics.

The YGTSS is a comprehensive evaluation of various aspects and severityof motor and phonic tics. In one aspect, each of five categories—number,frequency, intensity, complexity, and interference—is scored from 0 to 5for both motor and phonic tics, producing a tic severity score of 0 to25 for each of Vocal Tic Severity Score (VTSS) and Motor Tic SeverityScore (MTSS). Added together, these comprise the total tic severity(TTS) score. Separately, impairment of the patient's life is scored on ascale of 0 to 50, wherein 0 indicates no impairment, 10 is minimal, 20is mild, 30 is moderate, 40 is marked, and 50 is severe, yielding animpairment score. When the Impairment score is added to the TTS score,this comprises the complete Global Severity Score (GSS) of the YGTSS.

The Tourette Syndrome Patient Global Impression of Change (TS-PGIC) is aseven-point scale in which −3 indicates very much worse, −2 indicatesmuch worse, −1 indicated minimally worse, 0 indicated no change, 1indicates minimally improved, 2 indicates much improved, and 3 indicatesvery much improved.

The GTS-QOL consists of two parts. The first part is typically atwenty-seven question assessment of various aspects of how tics affectthe subject's life, each to be rated on a five-choice scale of noproblem, slight problem, moderate problem, marked problem, or severeproblem. The second part is a simple rating of the subject's lifesatisfaction, where 100 is extremely satisfied and 0 is extremelydissatisfied.

The Tic-Free Interval is a five-point scale in which 1 indicates aninterval of at least one day since the last tic, 2 indicates an intervalof between 6 hours to less than one day since the last tic, 3 indicatesan interval of between one hour and less than 6 hours since the lasttic, 4 indicates an interval of between five minutes to less than onehour since the last tic, and 5 indicates less than five minutes sincethe last tic.

The term “VMAT2” refers to vesicular monoamine transporter 2, anintegral membrane protein that acts to transport monoamines—particularlyneurotransmitters such as dopamine, norepinephrine, serotonin, andhistamine—from cellular cytosol into synaptic vesicles.

The term “VMAT2-mediated disorder,” refers to a disorder that ischaracterized by abnormal VMAT2 activity. A VMAT2-mediated disorder maybe completely or partially mediated by modulating VMAT2. In particular,a VMAT2-mediated disorder is one in which inhibition of VMAT2 results insome effect on the underlying disorder e.g., administration of a VMAT2inhibitor results in some improvement in at least some of the patientsbeing treated.

The term “VMAT2 inhibitor”, “inhibit VMAT2”, or “inhibition of VMAT2”refers to the ability of a compound disclosed herein to alter thefunction of VMAT2. A VMAT2 inhibitor may block or reduce the activity ofVMAT2 by forming a reversible or irreversible covalent bond between theinhibitor and VMAT2 or through formation of a noncovalently boundcomplex. Such inhibition may be manifest only in particular cell typesor may be contingent on a particular biological event. The term “VMAT2inhibitor”, “inhibit VMAT2”, or “inhibition of VMAT2” also refers toaltering the function of VMAT2 by decreasing the probability that acomplex forms between a VMAT2 and a natural substrate

The compounds disclosed herein can exist as therapeutically acceptablesalts. The term “therapeutically acceptable salt,” as used herein,represents salts or zwitterionic forms of the compounds disclosed hereinwhich are therapeutically acceptable as defined herein. The salts can beprepared during the final isolation and purification of the compounds orseparately by reacting the appropriate compound with a suitable acid orbase. Therapeutically acceptable salts include acid and basic additionsalts.

Suitable acids for use in the preparation of pharmaceutically acceptablesalts include, but are not limited to, acetic acid, 2,2-dichloroaceticacid, acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, boric acid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamicacid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid,D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid,hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid,(+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid,maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid,methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid,saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid,stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaricacid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, andvaleric acid.

Suitable bases for use in the preparation of pharmaceutically acceptablesalts, including, but not limited to, inorganic bases, such as magnesiumhydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, orsodium hydroxide; and organic bases, such as primary, secondary,tertiary, and quaternary, aliphatic and aromatic amines, includingL-arginine, benethamine, benzathine, choline, deanol, diethanolamine,diethylamine, dimethylamine, dipropylamine, diisopropylamine,2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine,isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine,morpholine, 4-(2-hydroxyethyl)-morpholine, methyl amine, piperidine,piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine,pyridine, quinuclidine, quinoline, isoquinoline, secondary amines,triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

While it may be possible for the compounds of the subject invention tobe administered as the raw chemical, it is also possible to present themas a pharmaceutical composition. Accordingly, provided herein arepharmaceutical compositions which comprise one or more of certaincompounds disclosed herein, or one or more pharmaceutically acceptablesalts, prodrugs, or solvates thereof, together with one or morepharmaceutically acceptable carriers thereof and optionally one or moreother therapeutic ingredients. Proper formulation is dependent upon theroute of administration chosen. Any of the well-known techniques,carriers, and excipients may be used as suitable and as understood inthe art; e.g., in Remington's Pharmaceutical Sciences. Thepharmaceutical compositions disclosed herein may be manufactured in anymanner known in the art, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or compression processes. The pharmaceuticalcompositions may also be formulated as a modified release dosage form,including delayed-, extended-, prolonged-, sustained-, pulsatile-,controlled-, accelerated- and fast-, targeted-, programmed-release, andgastric retention dosage forms. These dosage forms can be preparedaccording to conventional methods and techniques known to those skilledin the art.

The compositions include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous, intraarticular,and intramedullary), intraperitoneal, transmucosal, transdermal, rectaland topical (including dermal, buccal, sublingual and intraocular)administration although the most suitable route may depend upon forexample the condition and disorder of the recipient. The compositionsmay conveniently be presented in unit dosage form and may be prepared byany of the methods well known in the art of pharmacy. Typically, thesemethods include the step of bringing into association a compound of thesubject invention or a pharmaceutically salt, prodrug, or solvatethereof (“active ingredient”) with the carrier which constitutes one ormore accessory ingredients. In general, the compositions are prepared byuniformly and intimately bringing into association the active ingredientwith liquid carriers or finely divided solid carriers or both and then,if necessary, shaping the product into the desired formulation.

Formulations of the compounds disclosed herein suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. The active ingredient mayalso be presented as a bolus, electuary or paste.

Pharmaceutical preparations which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets may optionally becoated or scored and may be formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In addition, stabilizers may be added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. The formulations may be presentedin unit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in powder form or in a freeze-dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example, saline or sterile pyrogen-free water,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Formulations for parenteral administration include aqueous andnon-aqueous (oily) sterile injection solutions of the active compoundswhich may contain antioxidants, buffers, bacteriostats and solutes whichrender the formulation isotonic with the blood of the intendedrecipient; and aqueous and non-aqueous sterile suspensions which mayinclude suspending agents and thickening agents. Suitable lipophilicsolvents or vehicles include fatty oils such as sesame oil, or syntheticfatty acid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter, polyethylene glycol, or otherglycerides.

Certain compounds disclosed herein may be administered topically, thatis by non-systemic administration. This includes the application of acompound disclosed herein externally to the epidermis or the buccalcavity and the instillation of such a compound into the ear, eye andnose, such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral,intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin tothe site of inflammation such as gels, liniments, lotions, creams,ointments or pastes, and drops suitable for administration to the eye,ear or nose.

For administration by inhalation, compounds may be delivered from aninsufflator, nebulizer pressurized packs or other convenient means ofdelivering an aerosol spray. Pressurized packs may comprise a suitablepropellant such as dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Alternatively, foradministration by inhalation or insufflation, the compounds according tothe invention may take the form of a dry powder composition, for examplea powder mix of the compound and a suitable powder base such as lactoseor starch. The powder composition may be presented in unit dosage form,in for example, capsules, cartridges, gelatin or blister packs fromwhich the powder may be administered with the aid of an inhalator orinsufflator.

Preferred unit dosage formulations are those containing an effectivedose, as herein below recited, or an appropriate fraction thereof, ofthe active ingredient.

Compounds may be administered orally or via injection at a dose of from0.1 to 500 mg/kg per day. The dose range for adult humans is generallyfrom 5 mg to 2 g/day. Tablets or other forms of presentation provided indiscrete units may conveniently contain an amount of one or morecompounds which is effective at such dosage or as a multiple of thesame, for instance, units containing 5 mg to 500 mg, usually around 10mg to 200 mg.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

In certain embodiments, the compounds disclosed herein may be formulatedor administered using any of formulations and methods disclosed in U.S.patent application Ser. No. 14/030,322, filed Sep. 18, 2013, which ishereby incorporated by reference in its entirety.

The compounds can be administered in various modes, e.g. orally,topically, or by injection. The precise amount of compound administeredto a patient will be the responsibility of the attendant physician. Thespecific dose level for any particular patient will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, general health, sex, diets, time ofadministration, route of administration, rate of excretion, drugcombination, the precise disorder being treated, and the severity of thedisorder being treated. Also, the route of administration may varydepending on the disorder and its severity.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the compounds may beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisorder.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the compounds may be given continuouslyor temporarily suspended for a certain length of time (i.e., a “drugholiday”).

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disorder is retained.Patients can, however, require intermittent treatment on a long-termbasis upon any recurrence of symptoms.

Disclosed herein are methods of treating a VMAT2-mediated disordercomprising administering to a subject having or suspected of having sucha disorder, a therapeutically effective amount of a compound asdisclosed herein or a pharmaceutically acceptable salt, solvate, orprodrug thereof.

VMAT2-mediated disorders, include, but are not limited to, chronichyperkinetic movement disorders, Huntington's disease, hemiballismus,senile chorea, tic disorders, tardive dyskinesia, dystonia, Tourettesyndrome, depression, cancer, rheumatoid arthritis, psychosis, multiplesclerosis, asthma, and/or any disorder which can lessened, alleviated,or prevented by administering a VMAT2 inhibitor.

Also disclosed herein are methods of treating abnormal muscularactivity, abnormal involuntary movement, or movement disorders,comprising administering to a subject having or suspected of having sucha disorder, a therapeutically effective amount of a compound asdisclosed herein or a pharmaceutically acceptable salt, solvate, orprodrug thereof.

Movement disorders include akathisia, akinesia, ataxia, athetosis,ballismus, bradykinesia, cerebral palsy, chorea, corticobasaldegeneration, dyskinesias (e.g., paroxysmal), dystonia (general,segmental, focal) including blepharospasm, writer's cramp (limbdystonia), laryngeal dystonia (spasmodic dysphonia), and oromandibulardystonia, essential tremor, geniospasm, hereditary spastic paraplegia,Huntington's Disease, multiple system atrophy (Shy Drager Syndrome),myoclonus, Parkinson's Disease, Parkinson's disease levodopa-induceddyskinesia, parkinsonism, progressive supranuclear palsy, restless legssyndrome, Rett Syndrome, spasmodic torticollis (cervical dystonia),spasticity due to stroke, cerebral palsy, multiple sclerosis, spinalcord or brain injury, stereotypic movement disorder, stereotypy,Sydenham's Chorea, synkinesis, tardive dyskinesia, tics, Tourettesyndrome, and Wilson's Disease.

In certain embodiments, a method of treating abnormal muscular activity,abnormal involuntary movement, or movement disorder comprisesadministering to the subject a therapeutically effective amount of acompound as disclosed herein, or a pharmaceutically acceptable salt,solvate, or prodrug thereof, so as to affect: (1) decreasedinter-individual variation in plasma levels of the compound or ametabolite thereof; (2) increased average plasma levels of the compoundor decreased average plasma levels of at least one metabolite of thecompound per dosage unit; (3) decreased inhibition of, and/or metabolismby at least one cytochrome P₄₅₀ or monoamine oxidase isoform in thesubject; (4) decreased metabolism via at least onepolymorphically-expressed cytochrome P₄₅₀ isoform in the subject; (5) atleast one statistically-significantly improved disorder-control and/ordisorder-eradication endpoint; (6) an improved clinical effect duringthe treatment of the disorder, (7) prevention of recurrence, or delay ofdecline or appearance, of abnormal alimentary or hepatic parameters asthe primary clinical benefit, or (8) reduction or elimination ofdeleterious changes in any diagnostic hepatobiliary function endpoints,as compared to the corresponding non-isotopically enriched compound.

In certain embodiments, inter-individual variation in plasma levels ofthe compounds as disclosed herein, or metabolites thereof, is decreased;average plasma levels of the compound as disclosed herein are increased;average plasma levels of a metabolite of the compound as disclosedherein are decreased; inhibition of a cytochrome P₄₅₀ or monoamineoxidase isoform by a compound as disclosed herein is decreased; ormetabolism of the compound as disclosed herein by at least onepolymorphically-expressed cytochrome P₄₅₀ isoform is decreased; bygreater than about 5%, greater than about 10%, greater than about 20%,greater than about 30%, greater than about 40%, or by greater than about50% as compared to the corresponding non-isotopically enriched compound.

Plasma levels of the compound as disclosed herein, or metabolitesthereof, may be measured using the methods described by Li et al. RapidCommunications in Mass Spectrometry 2005, 19, 1943-1950; Jindal, et al.,Journal of Chromatography, Biomedical Applications 1989, 493(2), 392-7;Schwartz, et al., Biochemical Pharmacology 1966, 15(5), 645-55; Mehvar,et al., Drug Metabolism and Disposition 1987, 15(2), 250-5; Roberts etal., Journal of Chromatography, Biomedical Applications 1981, 226(1),175-82; and any references cited therein or any modifications madethereof.

Examples of cytochrome P450 isoforms in a mammalian subject include, butare not limited to, CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6,CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2,CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11,CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1,CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2,CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39,CYP46, and CYP51.

Examples of monoamine oxidase isoforms in a mammalian subject include,but are not limited to, MAOA, and MAOB.

The inhibition of the cytochrome P450 isoform is measured by the methodof Ko et al. (British Journal of Clinical Pharmacology, 2000, 49,343-351). The inhibition of the MAOA isoform is measured by the methodof Weyler et al. (J. Biol Chem. 1985, 260, 13199-13207). The inhibitionof the MAOB isoform is measured by the method of Uebelhack et al.(Pharmacopsychiatry, 1998, 31, 187-192).

Examples of polymorphically-expressed cytochrome P450 isoforms in amammalian subject include, but are not limited to, CYP2C8, CYP2C9,CYP2C19, and CYP2D6.

The metabolic activities of liver microsomes, cytochrome P450 isoforms,and monoamine oxidase isoforms are measured by the methods describedherein.

Examples of improved disorder-control and/or disorder-eradicationendpoints, or improved clinical effects include, but are not limited to:

-   -   b. improved Unified Huntington's Disease Rating Scale (UHDRS)        scores;    -   c. improved Total Maximal Chorea (TMC) Scores of the UHDRS;    -   d. improved Total Motor Scores (TMS) of the UHDRS;    -   e. improved Patient Global Impression of Change (PGIC) scores;    -   f. improved Clinical Global Impression of Change (CGIC) scores;    -   g. improved Unified Parkinson's Disease Rating Scale scores,        including the dysarthria score;    -   h. improved Abnormal Involuntary Movement Scale (AIMS) scores;    -   i. improved Goetz Dyskinesia Rating Scale scores;    -   j. improved Unified Dyskinesia Rating Scale scores;    -   k. improved PDQ-39 Parkinson's Disease Questionnaire scores;    -   l. improved Global Primate Dyskinesia Rating Scale scores;    -   m. improved Berg Balance Test scores;    -   n. improved Physical Functioning Scale of the SF-36 scores;    -   o. reduced Hospital Anxiety and Depression Scale (HADS) scores;    -   p. reduced Columbia Suicide Severity Rating Scale (C-SSRS)        scores;    -   q. improved Swallowing Disturbance Questionnaire (SDQ) scores;    -   r. improved (reduced) Barnes Akathisia Rating Scale (BARS)        scores;    -   s. reduced Epworth Sleepiness Scale (ESS) scores;    -   t. improved modified Craniocervical Dystonia 24 (CDQ-24) score;    -   u. Montreal Cognitive Assessment (MoCA);    -   v. improved Yale Global Tic Severity Scale (YGTSS) scores,        including Motor Tic Severity, Vocal Tic Severity, Total Tic        Severity Score (TTS) Impairment, and Global Severity (GSS)        scores thereof;    -   w. improved (reduced) Total Tic Severity Score (TTS);    -   x. improved Tourette Syndrome Clinical Global Impression        (TS-CGI) score;    -   y. improved Patient Global Impression of Severity in Tourette        Syndrome (TS-PGIS) score;    -   z. Children's Depression Inventory 2 (CDI-2; Parent and        Self-report versions);    -   aa. Children's Columbia Suicide Severity Rating Scale (C-SSRS);    -   bb. Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS)        score;    -   cc. Gilles de la Tourette Syndrome—Quality of Life (GTS-QOL),        including the physical/activities of daily living subscale        score, the overall life satisfaction score as measured by the        visual analog scale (VAS), the psychological subscale score,        obsessive-compulsive subscale score, and/or the cognitive        subscale score thereof;

Examples of diagnostic hepatobiliary function endpoints include, but arenot limited to, alanine aminotransferase (“ALT”), serum glutamic-pyruvictransaminase (“SGPT”), aspartate aminotransferase (“AST” or “SGOT”),ALT/AST ratios, serum aldolase, alkaline phosphatase (“ALP”), ammonialevels, bilirubin, gamma-glutamyl transpeptidase (“GGTP,” “γ-GTP,” or“GGT”), leucine aminopeptidase (“LAP”), liver biopsy, liverultrasonography, liver nuclear scan, 5′-nucleotidase, and blood protein.Hepatobiliary endpoints are compared to the stated normal levels asgiven in “Diagnostic and Laboratory Test Reference”, 4^(th) edition,Mosby, 1999. These assays are run by accredited laboratories accordingto standard protocol.

Besides being useful for human treatment, certain compounds andformulations disclosed herein may also be useful for veterinarytreatment of companion animals, exotic animals and farm animals,including mammals, rodents, and the like. More preferred animals includehorses, dogs, and cats.

Combination Therapy

The compounds disclosed herein may also be combined or used incombination with other agents useful in the treatment of VMAT2-mediateddisorders. Or, by way of example only, the therapeutic effectiveness ofone of the compounds described herein may be enhanced by administrationof an adjuvant (i.e., by itself the adjuvant may only have minimaltherapeutic benefit, but in combination with another therapeutic agent,the overall therapeutic benefit to the patient is enhanced).

Such other agents, adjuvants, or drugs, may be administered, by a routeand in an amount commonly used therefor, simultaneously or sequentiallywith a compound as disclosed herein. When a compound as disclosed hereinis used contemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compounddisclosed herein may be utilized, but is not required.

In certain embodiments, the compounds disclosed herein can be combinedwith one or more dopamine precursors, including, but not limited to,levodopa.

In certain embodiments, the compounds disclosed herein can be combinedwith one or more DOPA decarboxylase inhibitors, including, but notlimited to, carbidopa.

In certain embodiments, the compounds disclosed herein can be combinedwith one or more catechol-O-methyl transferase (COMT) inhibitors,including, but not limited to, entacapone and tolcapone.

In certain embodiments, the compounds disclosed herein can be combinedwith one or more dopamine receptor agonists, including, but not limitedto, apomorphine, bromocriptine, ropinirole, and pramipexole.

In certain embodiments, the compounds disclosed herein can be combinedwith one or more neuroprotective agents, including, but not limited to,selegeline and riluzole.

In certain embodiments, the compounds disclosed herein can be combinedwith one or more NMDA antagonists, including, but not limited to,amantidine.

In certain embodiments, the compounds disclosed herein can be combinedwith one or more anti-psychotics, including, but not limited to,chlorpromazine, levomepromazine, promazine, acepromazine,triflupromazine, cyamemazine, chlorproethazine, dixyrazine,fluphenazine, perphenazine, prochlorperazine, thiopropazate,trifluoperazine, acetophenazine, thioproperazine, butaperazine,perazine, periciazine, thioridazine, mesoridazine, pipotiazine,haloperidol, trifluperidol, melperone, moperone, pipamperone,bromperidol, benperidol, droperidol, fluanisone, oxypertine, molindone,sertindole, ziprasidone, flupentixol, clopenthixol, chlorprothixene,thiothixene, zuclopenthixol, fluspirilene, pimozide, penfluridol,loxapine, clozapine, olanzapine, quetiapine, tetrabenazine, sulpiride,sultopride, tiapride, remoxipride, amisulpride, veralipride,levosulpiride, lithium, prothipendyl, risperidone, clotiapine,mosapramine, zotepine, pripiprazole, and paliperidone.

In certain embodiments, the compounds disclosed herein can be combinedwith one or more benzodiazepines (“minor tranquilizers”), including, butnot limited to alprazolam, adinazolam, bromazepam, camazepam, clobazam,clonazepam, clotiazepam, cloxazolam, diazepam, ethyl loflazepate,estizolam, fludiazepam, flunitrazepam, halazepam, ketazolam, lorazepam,medazepam, dazolam, nitrazepam, nordazepam, oxazepam, potassiumclorazepate, pinazepam, prazepam, tofisopam, triazolam, temazepam, andchlordiazepoxide.

In certain embodiments, the compounds disclosed herein can be combinedwith olanzapine or pimozide.

The compounds disclosed herein can also be administered in combinationwith other classes of compounds, including, but not limited to,anti-retroviral agents; CYP3A inhibitors; CYP3A inducers; proteaseinhibitors; adrenergic agonists; anti-cholinergics; mast cellstabilizers; xanthines; leukotriene antagonists; glucocorticoidstreatments; local or general anesthetics; non-steroidalanti-inflammatory agents (NSAIDs), such as naproxen; antibacterialagents, such as amoxicillin; cholesteryl ester transfer protein (CETP)inhibitors, such as anacetrapib; anti-fungal agents, such asisoconazole; sepsis treatments, such as drotrecogin-α; steroidals, suchas hydrocortisone; local or general anesthetics, such as ketamine;norepinephrine reuptake inhibitors (NRIs) such as atomoxetine; dopaminereuptake inhibitors (DARIs), such as methylphenidate;serotonin-norepinephrine reuptake inhibitors (SNRIs), such asmilnacipran; sedatives, such as diazepham; norepinephrine-dopaminereuptake inhibitor (NDRIs), such as bupropion;serotonin-norepinephrine-dopamine-reuptake-inhibitors (SNDRIs), such asvenlafaxine; monoamine oxidase inhibitors, such as selegiline;hypothalamic phospholipids; endothelin converting enzyme (ECE)inhibitors, such as phosphoramidon; opioids, such as tramadol;thromboxane receptor antagonists, such as ifetroban; potassium channelopeners; thrombin inhibitors, such as hirudin; hypothalamicphospholipids; growth factor inhibitors, such as modulators of PDGFactivity; platelet activating factor (PAF) antagonists; anti-plateletagents, such as GPIIb/IIIa blockers (e.g., abdximab, eptifibatide, andtirofiban), P2Y(AC) antagonists (e.g., clopidogrel, ticlopidine andCS-747), and aspirin; anticoagulants, such as warfarin; low molecularweight heparins, such as enoxaparin; Factor VIIa Inhibitors and FactorXa Inhibitors; renin inhibitors; neutral endopeptidase (NEP) inhibitors;vasopepsidase inhibitors (dual NEP-ACE inhibitors), such as omapatrilatand gemopatrilat; HMG CoA reductase inhibitors, such as pravastatin,lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin,nisvastatin, or nisbastatin), and ZD-4522 (also known as rosuvastatin,or atavastatin or visastatin); squalene synthetase inhibitors; fibrates;bile acid sequestrants, such as questran; niacin; anti-atheroscleroticagents, such as ACAT inhibitors; MTP Inhibitors; calcium channelblockers, such as amlodipine besylate; potassium channel activators;alpha-muscarinic agents; beta-muscarinic agents, such as carvedilol andmetoprolol; antiarrhythmic agents; diuretics, such as chlorothlazide,hydrochiorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichioromethiazide,polythiazide, benzothlazide, ethacrynic acid, tricrynafen,chlorthalidone, furosenilde, musolimine, bumetanide, triamterene,amiloride, and spironolactone; thrombolytic agents, such as tissueplasminogen activator (tPA), recombinant tPA, streptokinase, urokinase,prourokinase, and anisoylated plasminogen streptokinase activatorcomplex (APSAC); anti-diabetic agents, such as biguanides (e.g.metformin), glucosidase inhibitors (e.g., acarbose), insulins,meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride,glyburide, and glipizide), thiozolidinediones (e.g. troglitazone,rosiglitazone and pioglitazone), and PPAR-gamma agonists;mineralocorticoid receptor antagonists, such as spironolactone andeplerenone; growth hormone secretagogues; aP2 inhibitors;phosphodiesterase inhibitors, such as PDE III inhibitors (e.g.,cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil,vardenafil); protein tyrosine kinase inhibitors; antiinflammatories;antiproliferatives, such as methotrexate, FK506 (tacrolimus, Prograf),mycophenolate mofetil; chemotherapeutic agents; immunosuppressants;anticancer agents and cytotoxic agents (e.g., alkylating agents, such asnitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, andtriazenes); antimetabolites, such as folate antagonists, purineanalogues, and pyrridine analogues; antibiotics, such as anthracyclines,bleomycins, mitomycin, dactinomycin, and plicamycin; enzymes, such asL-asparaginase; farnesyl-protein transferase inhibitors; hormonalagents, such as glucocorticoids (e.g., cortisone),estrogens/antiestrogens, androgens/antiandrogens, progestins, andluteinizing hormone-releasing hormone anatagonists, and octreotideacetate; microtubule-disruptor agents, such as ecteinascidins;microtubule-stablizing agents, such as pacitaxel, docetaxel, andepothilones A-F; plant-derived products, such as vinca alkaloids,epipodophyllotoxins, and taxanes; and topoisomerase inhibitors;prenyl-protein transferase inhibitors; and cyclosporins; steroids, suchas prednisone and dexamethasone; cytotoxic drugs, such as azathiprineand cyclophosphamide; TNF-alpha inhibitors, such as tenidap; anti-TNFantibodies or soluble TNF receptor, such as etanercept, rapamycin, andleflunimide; and cyclooxygenase-2 (COX-2) inhibitors, such as celecoxiband rofecoxib; and miscellaneous agents such as, hydroxyurea,procarbazine, mitotane, hexamethylmelamine, gold compounds, platinumcoordination complexes, such as cisplatin, satraplatin, and carboplatin.

Thus, in another aspect, certain embodiments provide methods fortreating VMAT2-mediated disorders in a subject in need of such treatmentcomprising administering to said subject an amount of a compounddisclosed herein effective to reduce or prevent said disorder in thesubject, in combination with at least one additional agent for thetreatment of said disorder. In a related aspect, certain embodimentsprovide therapeutic compositions comprising at least one compounddisclosed herein in combination with one or more additional agents forthe treatment of VMAT2-mediated disorders.

General Synthetic Methods for Preparing Compounds

The compounds as disclosed herein can be prepared by methods known toone of skill in the art and routine modifications thereof, and/orfollowing procedures similar to those described in US 20100130480(paragraphs [0093]-[0121]), US 20120003330 (paragraphs [0104]-[0162]),WO 2005077946; WO 2008/058261; EP 1716145; Lee et al., J. Med. Chem.,1996, (39), 191-196; Kilbourn et al., Chirality, 1997, (9), 59-62; Boldtet al., Synth. Commun., 2009, (39), 3574-3585; Rishel et al., J. Org.Chem., 2009, (74), 4001-4004; DaSilva et al., Appl. Radiat. Isot., 1993,44(4), 673-676; Popp et al., J. Pharm. Sci., 1978, 67(6), 871-873;Ivanov et al., Heterocycles 2001, 55(8), 1569-1572; U.S. Pat. Nos.2,830,993; 3,045,021; WO 2007130365; WO 2008058261, which are herebyincorporated in their entirety, and references cited therein and routinemodifications thereof.

Isotopic hydrogen can be introduced into a compound as disclosed hereinby synthetic techniques that employ deuterated reagents, wherebyincorporation rates are pre-determined; and/or by exchange techniques,wherein incorporation rates are determined by equilibrium conditions,and may be highly variable depending on the reaction conditions.Synthetic techniques, where tritium or deuterium is directly andspecifically inserted by tritiated or deuterated reagents of knownisotopic content, may yield high tritium or deuterium abundance, but canbe limited by the chemistry required. Exchange techniques, on the otherhand, may yield lower tritium or deuterium incorporation, often with theisotope being distributed over many sites on the molecule.

In certain embodiments, specific examples of compounds of the presentinvention include a compound selected from the list described inparagraph [0122] of US 20100130480 and paragraph [0163] of US20120003330, which are hereby incorporated by reference.

Changes in the in vitro metabolic properties of certain of the compoundsdisclosed herein as compared to their non-isotopically enriched analogsand methods of determining such changes have been described in paragraph[0125] of US 20100130480 and paragraphs [0165]-[0185] of US 20120003330,which are hereby incorporated by reference.

Formulations

Compounds may be formulated for use in the dosage regimens and methodsdisclosed herein by methods known in the art, e.g., as disclosed inUS2014/0336386. Examples of these formulations are provided below.

15 mg d₆-Tetrabenazine Gastro-Erosional Extended Release (Small Tablet)(Formulation A). Table 1 below discloses the elements of a 350 mg totalweight gastro-erosional granulation formulation tablet comprising 15 mg(RR,SS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d₃)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one.

TABLE 1 Material mg/tab % d₆-Tetrabenazine (milled) 15.0 4.3 MannitolPowder 185.4 53.0 Microcrystalline Cellulose 61.8 17.7 PVP K29/32 14.04.0 Tween 80 (Polysorbate 80) 3.8 1.1 Mannogem ® EZ (spray driedmannitol) 31.5 9.0 POLYOX ® N60K 35.0 10.0 Magnesium Stearate 3.5 1.0Totals: 350.0 100.0

d₆-Tetrabenazine (milled) is combined along with Mannitol Powder,Microcrystalline Cellulose, PVP K29/32 and Tween 80 (Polysorbate 80)into a high shear granulator and initially dry mixed at high impellerand chopper speed for 5 minutes. While mixing at high impeller speed andlow chopper speed, Purified Water is added to the mixing powders togranulate the material. Additional mixing and water addition with highimpeller and high chopper speed continues until the desired granulationend-point is achieved. The resulting granulation is wet screened tobreak up any oversized agglomerates and the material is added to a fluidbed drier and dried at 60° C. until the desired L.O.D. (loss on drying)is achieved. The dried material is sieved through a #20 mesh screen andthe oversized material is milled to a particle size of just under 20mesh in size. The dried and sized material is combined with Spray DriedMannitol and POLYOX® N60K into a diffusive mixer (V-Blender) where it isblended for 15 minutes. Magnesium Stearate is then passed through a #30mesh screen and added to the blended material in the V-Blender. Thecontents are then lubricated for 3 minutes and discharged for tabletcompression. Using a rotary tablet press fitted with punches and dies ofthe desired shape and size, the lubricated blend is compressed intotablets of a theoretical weight of 350 mg.

7.5 mg d₆-Tetrabenazine Gastro-Erosional Extended Release (Small Tablet)(Formulation A). Table 2 below discloses the elements of a 350 mg totalweight gastro-erosional granulation formulation tablet comprising 7.5 mgd₆-tetrabenazine. Same process as described for Example 1.

TABLE 2 Material mg/tab % d₆-Tetrabenazine (milled) 7.5 2.1 MannitolPowder 191.0 54.6 Microcrystalline Cellulose 63.7 18.2 PVP K29/32 14.04.0 Tween 80 (Polysorbate 80) 3.8 1.1 Mannogem EZ (spray dried mannitol)31.5 9.0 POLYOX ® N60K 35.0 10.0 Magnesium Stearate 3.5 1.0 Totals:350.0 100.0

15 mg d₆-Tetrabenazine Gastro-Retentive Extended Release (Large Tablet)(Formulation B). Table 3 below discloses the elements of a 700 mg totalweight gastro-retentive formulation tablet comprising 15 mgd₆-tetrabenazine. The gastro-retentive tablet is an elongated capsulehaving dimensions of approximately 0.7087 in. long by 0.3071 in. wide,having rounded ends with a cup depth of 0.0540 in. on each opposingside.

TABLE 3 Material mg/tab % d₆-Tetrabenazine (milled) 15.0 2.1 MannitolPowder 357.5 51.1 Microcrystalline Cellulose 119.0 17.0 PVP K29/32 26.03.7 Tween 80 (Polysorbate 80) 7.5 1.1 Mannogem EZ (spray dried mannitol)45.5 6.5 POLYOX ® N60K 122.5 17.5 Magnesium Stearate 7.0 1.0 Totals:700.0 100.0

7.5 mg d₆-Tetrabenazine Gastro-Retentive Extended Release (Large Tablet)(Formulation B). Table 4 below discloses the elements of a 700 mg totalweight gastro-retentive formulation tablet comprising 7.5 mgd₆-tetrabenazine. The gastro-retentive tablet is an elongated capsulehaving dimensions of approximately 0.7087 in. long by 0.3071 in. wide,having rounded ends with a cup depth of 0.0540 in. on each opposingside. Same process as described for Example 1. But theoreticalcompression weight is 700 mg.

TABLE 4 Material mg/tab % d₆-Tetrabenazine (milled) 7.5 1.1 MannitolPowder 363.0 51.9 Microcrystalline Cellulose 121.0 17.3 PVP K29/32 26.03.7 Tween 80 (Polysorbate 80) 7.5 1.1 Mannogem ® EZ (spray driedmannitol) 45.5 6.5 POLYOX ® N60K 122.5 17.5 Magnesium Stearate 7.0 1.0Totals: 700.0 100.0

6 mg d₆-Tetrabenazine Immediate Release Tablet. Table 5 below disclosesthe elements of a 125 mg total weight immediate-release tabletcomprising 6 mg d₆-tetrabenazine.

TABLE 5 Material mg/tab % d₆-Tetrabenazine (milled) 6.0 4.8 MannitolPowder 75.0 60.0 Microcrystalline Cellulose 25.0 20.0 Sodium StarchGlycolate 2.5 2.0 PVP K29/32 6.0 4.8 Tween 80 (Polysorbate 80) 1.0 0.8Mannogem ® EZ (spray dried mannitol) 5.8 4.6 Sodium Starch Glycolate 2.52.0 Magnesium Stearate 1.2 1.0 Totals: 125.0 100.0

d₆-Tetrabenazine (milled) is combined along with Mannitol Powder,Microcrystalline Cellulose, Sodium Starch Glycolate, PVP K29/32 andTween 80 (Polysorbate 80) into a high shear granulator and initially drymixed at high impeller and chopper speed for 5 minutes. While mixing athigh impeller speed and low chopper speed, Purified Water is added tothe mixing powders to granulate the material. Additional mixing andwater addition with high impeller and high chopper speed continues untilthe desired granulation end-point is achieved. The resulting granulationis wet screened to break up any oversized agglomerates and the materialis added to a fluid bed drier and dried at 60° C. until the desiredL.O.D. (loss on drying) is achieved. The dried material is sievedthrough a #20 mesh screen and the oversized material is milled to aparticle size of just under 20 mesh in size. The dried and sizedmaterial is combined with Spray Dried Mannitol and Sodium StarchGlycolate.

In all of the methods and compositions disclosed herein usingdeutetrabenazine, the deutetrabenazine may be administered or formulatedas part of a pharmaceutical composition as disclosed in tables 1-5above.

Clinical Trials and Results First-HD

First-HD was a randomized, double-blind, placebo-controlled,parallel-group study designed to evaluate the efficacy, safety, andtolerability of deutetrabenazine in subjects with chorea associated withHD. This trial was conducted in the United States and Canada, incollaboration with the Huntington Study Group.

Study Design

Subjects in First-HD were treated with deutetrabenazine or placebo,starting at 6 mg once per day and titrating weekly to doses of up to 24mg twice per day (48 mg total maximum daily dose). A total of 90subjects (45 in each group) were enrolled for evaluation over 13 weeks.Subjects were individually titrated to an optimal dose over up to eightweeks, received maintenance therapy at the optimal dose for four weeks,and were taken off study medication in the final week of the trial.

Subject Disposition and Demographic and Baseline Characteristics

Of the 90 subjects randomized, 87 subjects completed the study. Thestudy population was typical for subjects with chorea associated withHD. At baseline, the mean age of the subjects was 53.7 years. Themajority of subjects were white (92.2%) and male (55.6%). The mean CAGrepeat length among the subject population was 43.9. At baseline, themean TMC score was 12.7 in the overall population (range 8.0-19.5).

Study Endpoints and Measurements

The primary efficacy endpoint for the study was the change from baselineto maintenance therapy (average of Week 9 and Week 12 values) in themaximal chorea score of the UHDRS. The total maximal score, or TMC, is aclinician-based, quantitative assessment of chorea in seven bodyregions: face, mouth/tongue, trunk, and the four extremities, withhigher scores representing more severe chorea. This is the same endpointthat was accepted by the FDA when it considered and approvedtetrabenazine in 2008 (NDA 21894).

The total motor score (TMS) of the UHDRS was prespecified as anadditional efficacy endpoint in First-HD. The TMS assesses all the motorfeatures of HD, including items addressing characteristic motorabnormalities other than chorea, such as dystonia, gait, parkinsonism,and postural instability.

The clinical relevance of the change in the TMC score was assessed withfour prespecified secondary endpoints that assessed changes frombaseline to end of treatment (Week 12). These secondary endpoints weretested in a hierarchical manner:

1. Treatment success based on patient global impression of change(PGIC);

2. Treatment success based on clinical global impression of change(CGIC);

3. Physical Functioning Scale of the SF-36; and

4. Balance, as assessed by the Berg Balance Test (BBT).

The PGIC and CGIC are single-item questionnaires that ask the subjectand investigator, respectively, to assess a subject's overall HDsymptoms at specific visits after initiating therapy. Both assessmentsuse a 7-point Likert Scale, with responses ranging from Very Much Worse(—3) to Very Much Improved (+3) to assess overall response to therapy.Patients and clinicians were asked, “With respect to your (or thesubject's) overall Huntington's disease symptoms, how would you describeyourself (or the subject) compared to immediately before starting studymedication.” Treatment success according to these scales was defined asa rating of Much Improved or Very Much Improved at Week 12. Subjects whodid not have a response at Week 12 were assumed to be treatmentfailures.

Adverse events (AE) and their potential association with treatment werealso monitored. Categories of AEs of particular focus included thoseknown to be associated with tetrabenazine use:

-   -   Psychiatric disorders: insomnia, depression/agitated depression,        abnormal dreams, agitation, anxiety, suicidal ideation,        compulsions, impulsive behavior, and sleep disorders;    -   Nervous system disorders: somnolence, dizziness,        akathisia/restlessness, cognitive disorders, drooling,        dyskinesia, migraine, headache, loss of consciousness, and        syncope (fainting);    -   General disorders: irritability, fatigue, gait disturbance,        chest pain, and hangover; and    -   Gastrointestinal disorders: diarrhea, dry mouth, constipation,        nausea, upper abdominal pain, dyspepsia, frequent bowel        movements, gastrointestinal pain, vomiting, dysphagia,        flatulence, and salivary hypersecretion.

In addition to AE reporting, rating scales were used to monitor forpotential subclinical toxicity due to excessive monoamine depletion.Such safety scales were employed in the tetrabenazine developmentprogram. These scales applied in First-HD included the Hospital Anxietyand Depression Scale (HADS), the Columbia Suicide Severity Rating Scale(C-SSRS), the Swallowing Disturbance Questionnaire (SDQ), the UnifiedParkinson's Disease Rating Scale (dysarthria item) (UPDRS [dysarthria]),the Barnes Akathisia Rating Scale (BARS), and the Epworth SleepinessScale (ESS). In addition, the UHDRS, which includes cognitive,behavioral, and functional measures, was performed at key visits.

The Swallowing Disturbance Questionnaire (SDQ) was used prospectively toassess swallowing impairment during the study, as dysphagia is a commonproblem in patients with HD. This 15-item assessment has been validatedin patients with Parkinson's disease and has been shown to be asensitive and accurate tool for identifying patients with swallowingdisturbances arising from different etiologies. The SDQ is recommendedby the National Institute of Neurological Disorders and Stroke Commondata elements for assessing swallowing impairment in Parkinson'sdisease, and thus is also relevant for patients with HD, given they mayhave bradykinesia and other parkinsonian symptoms as part of theirillness.

Minor fluctuations in vital signs (blood pressure, heart rate,respiratory rate, and temperature) were observed during the study.

Results

The mean dose at the end of treatment period was 39.7 mg (SD 9.3 mg,range 12-48 mg) in the deutetrabenazine group and 43. 3 mg (7.6 mg,range 12-48 mg) in the placebo group. Mean dosage for the 10deutetrabenazine group subjects with impaired CYP2D6 function (poormetabolizers or on strong CYP2D6 inhibiting medications) was 34.8 mg(3.8 mg, range 30-42 mg). The overall compliance rates were 94.1% and95.1% for placebo and deutetrabenazine groups, respectively.

Treatment with deutetrabenazine resulted in improvements in allendpoints and reduced incidence of adverse events. In the results below,DTBZ=deutetrabenazine, CI=confidence interval (based on thet-distribution); SD=standard deviation; Least squares means and p-valuewere obtained from a two-sided test of the effect of treatment from andanalysis of covariance model with a term for treatment and the baselinescore as covariate.

Total Maximal Chorea Score (TMC). Treatment with deutetrabenazineresulted in robust improvement in maximal chorea score. TMC score at agiven time point is determined from Item 12 of the UHDRS. Change in TMCis the difference between baseline and maintenance therapy values. Thebaseline value is the mean of the Screening and Day 0 values and themaintenance therapy value is the mean of the Week 9 and Week 12 values.For the primary endpoint, subjects receiving deutetrabenazine achieved asignificant reduction of 2.5 units on the TMC score from baseline tomaintenance therapy compared with placebo (p<0.0001). This reduction inmaximal chorea represented a reduction of 21 percentage points comparedwith placebo (p<0.0001). Deutetrabenazine (DTBZ) was administered atapproximately half the daily dose of tetrabenazine. The efficacy ofdeutetrabenazine was therefore achieved at about half the daily dose oftetrabenazine.

TABLE 6 Total Maximal Chorea Score-Change from Baseline to MaintenanceTherapy Change in Total Maxima Chorea Score Difference in Means DTBZPlacebo (DTBZ − Placebo and Statistic (N = 45) (N = 45) 95% CI) AbsoluteChange in Total Maximal Chorea Score (Primary Efficacy Endpoint) LeastSquares −4.4 (3.0) −1.9 (2.7) −2.5 (−3.7, −1.3) Mean (SD) p-value — —<0.0001 Percentage Change in Total Maximal Chorea Score (AdditionalEfficacy Endpoint) (%) Least Squares −37 (25.7) −16 (19.6) −21 (−30.5,−11.1) Mean (SD) p-value — — <0.0001

Total Motor Score (TMS). Additionally, a statistically significantimprovement in the TMS of 4.0 units, compared with placebo, wasobserved. The fact that the TMS improvement was greater in magnitudethan the TMC score improvement (—2.5 units), suggests a benefit ofdeutetrabenazine treatment on other motor symptoms of HD, in addition tothe reduction in chorea. The majority of this improvement was due tochorea, but the total maximal dystonia score also contributed, withdeutetrabenazine improving by 0.9 (SE 0.24) points versus placebo 0.1(SE 0.32) points (p=0.02). From baseline to maintenance therapy, TMCimproved by 37% in the deutetrabenazine groups vs. 16% improvement inthe placebo group (p<0.0001). Changes in other UHDRS motor componentsdid not differ significantly between treatment groups, including nosignificant difference in the changes in the parkinsonism subscore(finger taps; pronation/supination; rigidity; bradykinesia; gait; tandemwalking; and retropulsion pull test scores) between deutetrabenazine andplacebo groups.

TABLE 7 Total Motor Score-Change from Baseline to Maintenance TherapyDifference in Means DTBZ Placebo (DTBZ − Placebo) Statistic (N = 45) (N= 45) and 95% CI Least Squares Mean −7.4 (6.3) −3.4 (5.5) −4.0 (−6.5,−1.5) (SD) p-value — — 0.0023

Total Motor Score: comparison to tetrabenazine. In contrast, in a12-week placebo-controlled study, tetrabenazine was demonstrated toimprove the TMC score of the UHDRS but the tetrabenazine treatmentfailed to show statistically significant improvement in TMS (HuntingtonStudy Group, 2006). These results suggest that tetrabenazine controlschorea associated with HD, but patients may experience a possibledecline in motor function that offsets the observed benefit on chorea.

Conclusion. Therefore, deutetrabenazine may represent a superior choicefor treatment of movement disorders generally. It is noteworthy thatdeutetrabenazine achieved efficacy at about half the daily dose oftetrabenazine.

Patient Global Impression of Change (PGIC) and Clinical GlobalImpression of Change (CGIC). At end of therapy, 51% (23 of 45) ofdeutetrabenazine-treated subjects were much improved or very muchimproved based on the PGIC, compared with 20% (9 of 45) subjects in theplacebo group (p=0.0020). Similar findings were observed by the treatingphysicians, where 42% (19 of 45) deutetrabenazine-treated subjects wereassessed as having achieved treatment success based on the CGIC comparedwith 13% (6 of 45) subjects in the placebo group (p=0.0022). Theseresults indicate that deutetrabenazine-treated subjects experienced aclinically meaningful benefit on their overall symptoms of HD and theirtreating clinicians were also able to observe the benefit.

Improvement in these physician and patient assessment scores indicatethat the improvement measured by the TMC and TMS translated intoimprovement of HD symptoms and further supports the clinical benefit ofdeutetrabenazine.

TABLE 8 Treatment Success at End of Therapy Determined by PGIC and CGICDifference in Percentages for DTBZ Placebo Treatment Success (N = 45) (N= 45) (DTBZ − Placebo) and 95% CI (%) (%) (%) Patient Global Impressionof Change: Treatment Success at the End of Therapyb 51 20 31 (12.4,49.8) p-value^(c) — — 0.0020 Clinical Global Impression of Change:Treatment Success at the End of Therapy^(b) 42 13 29 (11.4, 46.4)p-value^(c) — — 0.0022

SF-36 Physical Functioning Score. The Physical Functioning Score of theSF-36 was selected as a key secondary endpoint because it is apatient-reported instrument that has been used in many disease statesand it assesses physical activities relevant to patients living with HD.The 10-item physical functioning score queries patients regardingself-care such as bathing, dressing, lifting or carrying groceries,climbing one or more flights of stairs, bending, kneeling, walking 100yards or more, and moderate to vigorous activities. The SF-36 physicalfunctioning score has been shown to measure impairment experienced bypeople living with HD.

The mean change from baseline to Week 12 in the SF-36 physicalfunctioning score is provided below, where deutetrabenazine treatedsubjects demonstrated a mean improvement of 0.74 in treated patientsover baseline, compared to a worsening of 3.61 units in the placebogroup (a difference of 4.3 units). In subjects with more severe choreaat baseline (TMC>the median of the population, or TMC>12; n=49), thebenefit of deutetrabenazine on physical functioning was more pronounced,with a mean improvement of 7.1 units over placebo (p=0.0075).

Change from Baseline to Week 12 on the SF-36 physical functioning scoreshowed that SD-809-treated subjects had greater improvement in physicalfunction compared with placebo-treated subjects (p=0.03). Analysis ofSF-36 by baseline severity of chorea indicated that SD-809 had a greaterbenefit in subjects with more severe chorea (p=0.0075). Given thepotential for chorea to interfere with basic motor skills, gait, andwalking it is not unexpected that subjects with more impaired functionwould experience greater benefit on this measure.

Given the significant negative impact that chorea has on the patient'squality of life and physical functioning, the statistically significantimprovement in the subjects' assessment of their ability to performactivities of daily living further supports the clinical benefit ofdeutetrabenazine.

TABLE 9 SF-36 Physical Functioning Score-Change from Baseline to Week 12Change in SF-36 Score from Baseline to Week 12 Difference in Means DTBZPlacebo (DTBZ − Placebo) Statistic (N = 45) (N = 45) and 95% CI N 45 43Least Squares 0.74 (9.773) −3.61 (9.669) 4.34 (0.41, 8.27) Mean (SD)p-value — — 0.0308

Berg Balance Test. The BBT is a 14-item assessment of balance that wasused to evaluate if reducing chorea had an impact on balance, since manymedications currently used to treat chorea may worsen balance. The BBTwas assessed as a safety measure and efficacy endpoint. As summarizedbelow, deutetrabenazine did not worsen balance at end of treatment, andin fact the data numerically favored deutetrabenazine, although theimprovement was not statistically significant (p=0.1415). In addition,there was no statistically significant difference betweendeutetrabenazine and placebo on the BBT observed during the course ofthe study.

TABLE 10 Change in Berg Balance Test Score from Baseline to Week 12Change in BBT Score from Baseline to Week 12 DTBZ Placebo Difference inMeans Statistic (N = 45) (N = 45) (DTBZ-Placebo) and 95% CI LeastSquares 2.2 (3.47) 1.3 (4.04) 1.0 (−0.3, 2.3) Mean (SD) p-value — —0.1415

Adverse Events. Deutetrabenazine was generally well tolerated. Theoverall rates of adverse events (AEs) were the same between thedeutetrabenazine and placebo groups, with (60.0%) of subjects in eachgroup experiencing at least one AE. There were no deaths in the study.There was one subject with two serious AEs (cholecystitis and agitateddepression) in the deutetrabenazine group, and one subject with oneserious AE (exacerbation of chronic obstructive pulmonary disease, orCOPD) in the placebo group. The same subject experiencing the seriousAEs in the deutetrabenazine group also reported suicidal ideation, whichwas not considered a serious AE, and subsequently withdrew from thestudy due to an AE of agitation. In the placebo group, one subjectreported suicidal ideation on the Columbia Suicide Severity Rating Scaleand one subject withdrew from the study due to an AE of atrialfibrillation. Evidence of good tolerability is further indicated by thesame rates of AEs leading to dose reduction, dose suspension andwithdrawal. Finally, CYP2D6 genetic status did not impact dosing in thisstudy or the rate of AE. As expected, poor metabolizers, either throughgenetics or concomitant medications, were dosed slightly lower andwithout additional AEs, supporting the notion that deutetrabenazinedosing may be managed clinically without reliance on expensivegenotyping.

TABLE 11 Overview of Treatment-Emergent Adverse Events DTBZ Placebo (N =45) (N = 45) Type of Event n (%) n (%) Any Treatment-Emergent AEs(TEAEs) 27 (60.0) 27 (60.0) Any Psychiatric Disorders TEAE  8 (17.8)  8(17.8) Any Nervous System Disorders TEAE  8 (17.8) 10 (22.2) Any SeriousTEAEs  1 (2.2)  1 (2.2) Any TEAEs Resulting in Dose Reduction  3 (6.7) 3 (6.7) Any TEAEs Resulting in Dose Suspension  1 (2.2)  1 (2.2) AnyTEAE that led to Withdrawal from the Study  1 (2.2)  1 (2.2)

Similar rates of AEs were also observed among the psychiatric andnervous system body systems, which are areas of particular importancefor patients with HD. The numbers of subjects reporting AEs in certainsystem organ classes of psychiatric, nervous system, gastrointestinaland other general disorders are listed in Table 12 below. These bodysystems are highlighted because they include many of the underlyingsymptoms observed in patients with HD and were also frequent AEsobserved with tetrabenazine. Deutetrabenazine-treated subjects had lowrates of insomnia, depression, anxiety, agitation, suicidal ideation,akathisia, irritability, and fatigue and these rates were similar to orlower than the incidence observed in placebo-treated subjects.Importantly, no AEs of parkinsonism or dysphagia were reported in thedeutetrabenazine group. The most common AE observed in thedeutetrabenazine group was somnolence, which was observed in 11.1% ofsubjects versus 4.4% in the placebo group, or a drug-placebo differenceof 6.7%.

TABLE 12 Treatment-Emergent Adverse Events System DTBZ Placebo Organ (N= 45) (N = 45) Class Preferred Term n (%) n (%) PSYCHIATRIC Insomnia 3(6.7) 2 (4.4) DISORDERS Depression/Agitated 2 (4.4) 3 (6.7) DepressionAbnormal Dreams 1 (2.2) 1 (2.2) Agitation 1 (2.2) 0 Anxiety 1 (2.2) 1(2.2) Suicidal Ideation 1 (2.2) 0 Compulsions 0 1 (2.2) ImpulsiveBehavior 0 1 (2.2) Sleep Disorder 0 3 (6.7) NERVOUS Somnolence 5 (11.1)2 (4.4) SYSTEM Dizziness 2 (4.4) 4 (8.9) DISORDERSAkathisia/Restlessness 1 (2.2) 1 (2.2) Cognitive Disorder 1 (2.2) 0Drooling 1 (2.2) 0 Dyskinesia 1 (2.2) 0 Migraine 1 (2.2) 0 Headache 0 3(6.7) Loss of Consciousness 0 1 (2.2) Syncope 0 1 (2.2) GENERALIrritability 3 (6.7) 6 (13.3) DISORDERS Fatigue 3 (6.7) 2 (4.4) Gaitdisturbance 1 (2.2) 0 Chest pain 1 (2.2) 0 Hangover 1 (2.2) 0 GASTRO-Diarrhea 4 (8.9) 0 INTESTINAL Dry mouth 4 (8.9) 3 (6.7) DISORDERSConstipation 2 (4.4) 1 (2.2) Nausea 1 (2.2) 2 (4.4) Abdominal pain upper1 (2.2) 0 Dyspepsia 1 (2.2) 0 Frequent bowel 1 (2.2) 0 movementsGastrointestinal pain 1 (2.2) 0 Vomiting 0 3 (6.7) Dysphagia 0 1 (2.2)Flatulence 0 1 (2.2) Salivary hypersecretion 0 1 (2.2)

Safety. In addition to AE reporting, rating scales were used to monitorfor potential subclinical toxicity due to excessive monoamine depletion.Such safety scales were employed in the tetrabenazine developmentprogram. These scales applied in First-HD included the Hospital Anxietyand Depression Scale (HADS), the Columbia Suicide Severity Rating Scale(C-SSRS), the Swallowing Disturbance Questionnaire (SDQ), the UnifiedParkinson's Disease Rating Scale (dysarthria item) (UPDRS [dysarthria]),the Barnes Akathisia Rating Scale (BARS), and the Epworth SleepinessScale (ESS). In addition, the UHDRS, which includes cognitive,behavioral, and functional measures, was performed at key visits.

These safety scales showed that deutetrabenazine did not causedepression, anxiety, suicidality, akathisia, somnolence, or difficultyspeaking, as between group difference on the scales were small and notclinically significant. In fact, swallowing function, which is animportant cause of morbidity and mortality in patients with HD, wasshown to significantly improve in deutetrabenazine-treated subjectscompared with placebo and was consistent with improvement seen in motorfunction. The clinical relevance of this improvement is described below.

Swallowing Disturbance. The Swallowing Disturbance Questionnaire (SDQ)was used prospectively to assess swallowing impairment during the study,as dysphagia is a common problem in patients with HD. This 15-itemassessment has been validated in patients with Parkinson's disease andhas been shown to be a sensitive and accurate tool for identifyingpatients with swallowing disturbances arising from different etiologies.The SDQ is recommended by the National Institute of NeurologicalDisorders and Stroke Common data elements for assessing swallowingimpairment in Parkinson's disease, and thus is also relevant forpatients with HD, given they may have bradykinesia and otherparkinsonian symptoms as part of their illness. FIG. 2 presents the meanchange from baseline in the SDQ by over time, demonstrating asignificant improvement in swallowing with deutetrabenazine treatment,compared with placebo.

Additional UHDRS Assessments. The UHDRS rating scale was assessedthroughout the First-HD Study to monitor for safety. Evaluation of theparkinsonism subscore of the UHDRS Motor Assessment (Part I) did notidentify evidence of parkinsonism in subjects treated withdeutetrabenazine or placebo, consistent with the absence ofextrapyramidal symptom AEs. These results were further supported by thelack of meaningful changes in either treatment group on the UPDRSdysarthria question.

The results of the UHDRS Cognitive Assessment (Part II) alsodemonstrated no meaningful changes from baseline or consistent trendsbetween treatment groups, indicative of no decline in cognitive functionwith treatment.

The UHDRS Behavioral Assessment (Part III) demonstrated improvement inthe in the mean total behavior score for deutetrabenazine-treatedsubjects compared with the placebo group, however the difference did notachieve statistical significance. Importantly, there was no worsening ofdepressed mood, apathy, self-esteem, irritability, aggressive behavior,suicidal thoughts, hallucinations, or delusions. The improvement in theoverall score was driven by differences in anxiety and compulsivebehavior (FIG. 4 A-C).

The UHDRS Functional Assessment Score (Part IV), Independence ScaleScore (Part V) and the Total Functional Capacity Score (Part VI), whichwere assessed at Baseline and again at Week 12, did not show clinicallyrelevant changes from baseline in either treatment group or differencesbetween the treatment groups.

Minor fluctuations in vital signs (blood pressure, heart rate,respiratory rate, and temperature) were observed during the study; thesechanges were generally similar in the deutetrabenazine and placebotreatment groups and were not assessed as clinically significant. Noconsistent between group differences were observed. In addition, therewas no evidence that hypotension, dizziness, or orthostasis wasassociated with deutetrabenazine treatment.

Body weight. Compared with the placebo group, deutetrabenazine treatmentled to a mean weight gain of approximately 2.1 kg over placebo (at week12, mean (SD) change in body weight of +1.8 (3.4) kg fordeutetrabenazine vs −0.30 (2.5) kg in placebo (treatment effect, +2.1kg). Weight gain correlates with improved treatment outcome and healthin chorea patients, and may result in part from reduced chorea (wherebythe improved swallowing may lead to better intake of food, which whencombined with less caloric energy used due to reduced abnormalinvoluntary movements, may translate into weight gain), in addition toimproved function or behavioral symptoms such as anxiety, which maysuppress appetite.

Adverse Events and Safety: comparison to tetrabenazine. The variablepharmacokinetics of tetrabenazine can affect its tolerability and limitits clinical use. The half-lives of the circulating active metabolites,α- and β-dihydrotetrabenazine, are short. These short half-livesnecessitate frequent dosing and result in large fluctuations in plasmaconcentrations. The high peak concentrations and variability in plasmalevels associated with tetrabenazine may contribute to the poortolerability that is often observed.

Accordingly, the prescribing information for tetrabenazine containsseveral warnings regarding adverse effects and the potential for safetyissues:

-   -   A boxed warning indicates that tetrabenazine increases the risk        of depression and suicidal thoughts and behavior (suicidality)        in patients with HD.    -   High rates of treatment-emergent adverse events were observed in        patients treated with tetrabenazine compared with        placebo-treated patients, including somnolence/sedation,        insomnia, depression, akathisia, anxiety, and fatigue (see Table        #13).    -   Dose escalation was discontinued or dosage of study drug was        reduced due to adverse events in 52% (28 of 54) of patients        randomized to tetrabenazine.    -   In the 12-week, randomized controlled trial of tetrabenazine,        adverse events suggestive of parkinsonism (e.g., parkinsonism,        bradykinesia, hypertonia, rigidity) were observed in 15% of        tetrabenazine patients compared with 0% of placebo patients.    -   A Warning and Precaution cites the risk of dysphagia, an        underlying symptom of HD and a known side effect of reduced        dopaminergic neurotransmission. Although low rates of dysphagia        were reported in the 12-week trial, in open-label studies,        dysphagia was observed in 8% to 10% of tetrabenazine-treated        patients, with some cases associated with aspiration pneumonia.        It is unclear whether these cases were associated with        treatment, however FDA expressed concern that events of        dysphagia, which can have devastating clinical consequences, may        have been significantly underestimated in the tetrabenazine NDA.        Of note, in a retrospective study of 98 patients treated with        tetrabenazine for hyperkinetic movement disorders, dysphagia was        observed in 19% of patients.    -   At 50 mg, tetrabenazine caused an approximately 8 ms mean        increase in QTc interval (90% two-sided Confidence Interval        [CI]: 5.0, 10.4 ms).

The safety profile of tetrabenazine observed in the 12-week, controlledtrial is reflected in the prescribing information, as summarized below.

TABLE 13 Treatment Emergent Adverse Reactions in Patients Treated withTetrabenazine Occurring with a Greater Frequency than Placebo in12-Week, Double-Blind, Placebo- Controlled Trial of TetrabenazineTetrabenazine Placebo (N = 54) (N = 30) Body System Preferred Term n (%)n (%) PSYCHIATRIC Sedation/ 17 (31) 1 (3) DISORDERS somnolence Insomnia12 (22) 0 Depression 10 (19) 0 Anxiety/anxiety  8 (15) 1 (3) aggravated  Irritability  5 (9) 1 (3) Appetite decreased  2 (4) 0 Obsessivereaction  2 (4) 0 CENTRAL & Akathisia 10 (19) 0 PERIPHERAL Balancedifficulty  5 (9) 0 NERVOUS SYSTEM Parkinsonism/  5 (9) 0 bradykines iaDizziness  2 (4) 0 Dysarthria  2 (4) 0 Gait unsteady  2 (4) 0 Headache 2 (4) 1 (3) GASTROINTESTINAL Nausea  7 (13) 2 (7) SYSTEM DISORDERSVomiting  3 (6) 1 (3) BODY AS A WHOLE Fatigue 12 (22) 4 (13) Fall  8(15) 4 (13) GENERAL Laceration (head)  3 (6) 0 Ecchymosis  3 (6) 0RESPIRATORY Upper respiratory  6 (11) 2 (7) SYSTEM tract DISORDERSinfection Shortness of breath  2 (4) 0 Bronchitis  2 (4) 0 URINARYSYSTEM Dysuria  2 (4) 0 DISORDERS

In comparison to deutetrabenazine, tetrabenazine appears to produce moreadverse effects.

ARC-HD

In a second clinical trial, a method for converting patients withadequate control of chorea with tetrabenazine to deutetrabenazinetreatment was implemented. Alternatives for Reducing Chorea inHuntington Disease (ARC-HD) was an open-label, single-arm study in whichsubjects with manifest HD who were receiving FDA-approved doses oftetrabenazine for the treatment of chorea or had successfully completedFirst-HD were invited to participate.

The study thus comprised two cohorts. The Rollover Cohort (75 subjects)successfully completed the First-HD study described above, including a1-week washout; the Switch Cohort (37 subjects) switched overnight fromstable dosing (≥8 weeks) with tetrabenazine to deutetrabenazine based ona conversion method designed to achieve comparable systemic exposure tototal α and β metabolites. Other key inclusion criteria for the studyincluded: diagnosed with manifest HD, as indicated by characteristicmotor examination features; a documented expanded cytosine adenineguanine (CAG) repeat (≥37) and Total Functional Capacity (TFC) score ≥5at or before Screening; able to ambulate without assistance for at least20 yards (assistive devices such as walker or cane permitted); andsubject has a reliable caregiver who interacts with the subject on adaily basis, oversees study drug administration, assures attendance atstudy visits, and participates in evaluations, as required. Keyexclusion criteria included serious untreated or undertreatedpsychiatric illness (e.g., depression) at Screening or Baseline;concomitant dopamine receptor antagonists, dopamine agonists, levodopa,reserpine, N-methyl-D-aspartate receptor antagonists, or monoamineoxidase inhibitors within 30 days of Screening or Baseline; and score≥11 on the depression subscale of the Hospital Anxiety and DepressionScale (HADS), a score of ≥11 on the Swallowing Disturbance Questionnaire(SDQ), or a Unified Parkinson's Disease Rating Scale (UPDRS) dysarthriascore of ≥3 at Screening or Baseline.

Participants were 58% male, 95% White, and had a mean age of 54 years.The mean (SD) TMC score at Baseline was 12.2 (4.6) and the mean (SD) CAGrepeat length was 44 (3.7)

Study Design

The guidance for investigators on conversion of subjects from stabledoses of tetrabenazine to deutetrabenazine in the ARC-HD Switch studywas designed to minimize the risk that dose conversion would result ineither loss of efficacy or increased adverse events. The conversionmethod applied was based on modeling and simulation of Phase 1pharmacokinetic data for deutetrabenazine and tetrabenazine. Theobjective of the pharmacokinetic analysis was to identify an initialdosing regimen of deutetrabenazine predicted to provide exposure atsteady state of the active α and β metabolites that was less than orequal to the predicted AUC at steady state of the active alpha and betametabolites of tetrabenazine, but with a lower Cmax.

In a Phase 1 single-center, open-label, crossover clinical trial, eachof 24 healthy volunteer subjects received single doses of 25 mg oftetrabenazine and 15 mg of deutetrabenazine. One of the objectives ofthe clinical trial was to evaluate and compare the safety ofdeutetrabenazine relative to tetrabenazine.

Subjects in the Switch cohort completed a full screening evaluation.Subjects who were eligible to enroll in the study were subsequentlyconverted from their tetrabenazine dose regimen to a deutetrabenazinedose regimen predicted to be comparable to their existing tetrabenazineregimen. Subjects received existing tetrabenazine regimen throughmidnight of Day 0 and switched to their assigned deutetrabenazineregimen the next morning (Day 1 of the study). The initial dose wasbased on a conversion method, defined by a Phase 1 pharmacokineticcomparison of deutetrabenazine and tetrabenazine suggesting an initialdose of deutetrabenazine that is approximately 50% of the existingtetrabenazine dose (Table 15). Following the first week ofdeutetrabenazine treatment, the dose of deutetrabenazine was allowed tobe adjusted upward or downward once per week in increments of 6 mg/dayuntil a dose that adequately controls chorea was identified, the subjectexperienced a protocol defined “clinically significant” adverse event,or the maximal allowable dose was reached. The investigator, inconsultation with the subject and caregiver, determined when an adequatelevel of chorea control had been achieved. If a subject experienced a“clinically significant” adverse event attributable to deutetrabenazine,the investigator determined if a dose reduction or suspension wasnecessary.

TABLE 15 Method for Converting Patients from Tetrabenazine todeutetrabenazine Therapy Incoming Initial Initial Total Total TotalDaily deutetra- Daily Daily benazine Dose Tetra- deutetra- RegimenSubsequent benazine benazine Morning Evening deutetrabenazine Dose DoseDose Dose Dosing Regimen 12.5 mg  6 mg  6 mg — Dose adjusted upward   25mg 12 mg  6 mg  6 mg or downward (6-mg/day 37.5 mg 18 mg  9 mg  9 mgincrements once per   50 mg 24 mg 12 mg 12 mg week) to achieve dose 62.5mg 30 mg 15 mg 15 mg that adequately controls   75 mg 36 mg 18 mg 18 mgchorea 87.5 mg 42 mg 21 mg 21 mg  100 mg 48 mg 24 mg 24 g

Subjects in the Rollover cohort completed a 1-week washout at theconclusion of First-HD, during which mean TMC scores returned tobaseline. The deutetrabenazine dose for these subjects was titrated froma starting dose of 6 mg per day to a dose that controlled chorea and waswell tolerated.

For both cohorts, oral tablets at strengths of 6 mg, 9 mg, and 12 mgwere used. Doses of 12 mg and higher were administered in two divideddoses approximately 10 hours apart. All study treatment regimens wereadministered orally with meals. The maximum total daily dose ofdeutetrabenazine was set at 72 mg per day, unless the subject wasreceiving a strong CYP2D6 inhibitor (e.g., paroxetine), in which casethe maximum total daily dose was 36 mg.

Subjects attended regular clinic visits to evaluate safety and establishan optimal dose. The investigator, in consultation with the subject andcaregiver, determined when an adequate level of chorea control wasachieved; the dose of DTBZ could be increased on a weekly basis untilthere was adequate control of chorea, the subject experienced a protocoldefined clinically significant adverse event, or the maximal allowabledose was reached. During long-term treatment, all subjects had regularcontact with the study site for evaluation of safety and chorea control.Long-term treatment will continue until deutetrabenazine becomescommercially available in the U.S.

A total of 37 subjects with chorea associated with HD that wasadequately controlled with tetrabenazine who had converted fromtetrabenazine to deutetrabenazine treatment in ARC-HD Switch wereincluded in an analysis conducted to assess maintenance of choreacontrol following dose conversion. The subjects included in the analysiswere each converted from tetrabenazine treatment to a deutetrabenazinedaily dose, administered twice daily, that was approximately 30% to 50%of their prior total daily tetrabenazine dose.

Results

Dose & Efficacy. Given the differences in prior therapy and expectedchanges in chorea control following initiation of deutetrabenazinetherapy in the two cohorts, efficacy data are summarized separately forthese two groups. Data from the two cohorts is provided below throughWeek 15. As this study is ongoing, data from subsequent weeks are stillbeing gathered and analyzed, and results comprise too few patients todraw meaningful conclusions at this stage.

Dose—Switch Cohort. The mean dose of TBZ at baseline was 42 mg and,after the overnight switch, the mean dose of deutetrabenazine was 20 mg.Mean daily doses of deutetrabenazine following the switch from TBZ aregiven below in Table 15.

TABLE 15 TBZ Dose at Baseline and DTBZ Dose Conversion and TitrationDTBZ Daily Dose (mg) TBZ Dose Day 1 at Baseline through Statistic (mg)Week 1 Week 4 Week 8 Week 15 n 37 37 36 22 15 Mean (SD) 42.1 (19.58)20.3 29.7 33.5 36.0 Dose (10.23) (10.44) (11.36) (14.70) Minimum, 12.5,100 6, 48 12, 48 12, 48 12, 60 Maximum

Dose—Rollover Cohort. Mean daily doses of deutetrabenazine followingwash-out and initial doses of 6 mg/day are given below in Table 16.

TABLE 16 DTBZ Daily Dose Titration DTBZ Daily Dose (mg) Statistic Week 2Week 4 Week 8 Week 15 n 62 56 44 34 Mean (SD) Dose 11.8 24.2 38.9 41.1(1.07) (4.57) (11.09) (9.24) Minimum, 6, 12 6, 36 6, 48 18, 48 Maximum

Total Maximal Chores (TMC)—Switch Cohort. One week following the switchto deutetrabenazine, at a time when subjects were still receiving theirinitial total daily deutetrabenazine dose, the mean total chorea scoredecreased by approximately one point from baseline (mean±standard error[SE] change from baseline was −0.72±2.6), indicating thatdeutetrabenazine maintained chorea control in these subjects. A subsetof 35 subjects also had chorea assessed four weeks after switching todeutetrabenazine. In this set of subjects, the mean (±SE) change frombaseline was −0.7±3.0 at Week 4, providing further demonstration ofmaintenance of chorea control. In addition, data from 21 patients wereavailable at Week 8; these data demonstrated change from baseline of−1.9±3.5 units on the TMC score; at week 15, −1.2±4.1 units. Results aregiven below in Table 17. A summary of the change in mean chorea scoreobserved and the mean daily dose of tetrabenazine or deutetrabenazinecorresponding to the chorea score is provided in FIG. 6.

TABLE 17 Total Maximal Chorea Score (Switch Cohort) Total Maximal ChoreaScore Time Mean (SD) Change from Point n Mean (SD) Score n Baselinep-value^(a) Baseline 37 12.47 (5.26) — — — Week 1 37 11.76 (5.11) 37−0.72 (2.59) 0.1007 Week 4 36 11.86 (5.23) 36 −0.74 (3.01) 0.1507 Week 821 10.10 (5.56) 21 −1.86 (3.52) 0.0252 Week 15 15 10.87 (5.99) 15 −1.17(4.07) 0.2850

Total Maximal Chores (TMC)—Rollover Cohort. At Week 2, a statisticallysignificant mean (SD) decrease from Baseline of 1.9 (3.0) units wasobserved (p<0.0001). This effect persisted through Week 15, at whichtime the mean (SD) decrease from baseline was 4.5 (5.0) units(p=0.0001). These results are consistent with those observed for DTBZ inFirst-HD. Results are given below in Table 18.

TABLE 18 Total Maximal Chorea Score (Rollover Cohort) Total MaximalChorea Score Time Mean (SD) Change from Point n Mean (SD) Score nBaseline p-value^(a) Baseline 71 12.0 (4.25) — — — Week 2 61 10.1 (3.41)58 −1.9 (2.95) <0.0001 Week 4 55  9.8 (3.69) 52 −2.5 (3.21) <0.0001 Week8 43  7.9 (3.91) 40 −4.5 (3.34) <0.0001 Week 15 34  7.9 (4.05) 33 −4.5(4.04) <0.0001

Total Motor Score (TMS)—Switch Cohort. Additionally, overall motorsymptoms, as assessed by the TMS, were maintained following doseconversion and appeared to improve at Week 8, as indicated by a mean(SD) change from baseline in TMS of −3.7 (7.8). Results are given belowin Table 19.

TABLE 19 Total Motor Score Over Time (Switch Cohort) Total Motor ScoreTime Mean (SD) Change from Point n Mean (SD) Score n Baselinep-value^(a) Baseline 37 38.49 (18.679) — — — Week 1 37 36.35 (18.043) 37−2.14 (5.414) 0.0218 Week 4 36 37.14 (19.516) 36 −1.85 (8.419) 0.1966Week 8 24 34.58 (18.268) 24 −3.73 (7.787) 0.0279 Week 15 15 35.00(22.984) 15  −1.93 (10.910) 0.5037

A summary of the change in mean chorea score observed and the mean dailydose of tetrabenazine or deutetrabenazine corresponding to the choreascore is provided in FIG. 7.

Total Motor Score (TMS)—Rollover Cohort. Statistically significant meandecreases in TMS from baseline were observed as early as Week 2 (3.9units; p<0.0001) and persisted through Week 15 (8.0 units; p=0.0001).Results are given below in Table 20.

TABLE 20 Total Motor Score (Rollover Cohort) Total Motor Score Time Mean(SD) Change from Point n Mean (SD) Score n Baseline p-value^(a) Baseline71 35.3 (16.34) — — — Week 2 61 32.4 (15.23) 58 −3.9 (6.67) <0.0001 Week4 55 32.1 (16.84) 52 −5.9 (7.88) <0.0001 Week 8 43 31.0 (18.07) 40 −8.3(8.58) <0.0001 Week 15 35 30.5 (17.70) 33 −8.0 (8.41) <0.0001

The fact that the mean TMS improvement ((—3.7 units at Week 8 in theSwitch cohort and −8.0 units at Week 15 in the Rollover cohort) wasgreater in magnitude than the mean TMC score improvement (—1.9 units atWeek 8 in the Switch cohort and −4.5 units at Week 15 in the Rollovercohort) suggests a benefit of DTBZ treatment on other motor symptoms ofHD, in addition to the reduction in chorea.

It is expected that other deuterium substituted tetrabenazines andvalbenazines will be efficacious in the treatment of chorea and othersymptoms associated with Huntington's disease and other movementdisorders, as well as abnormal involuntary movements generally.

Adverse Events. DTBZ was generally well tolerated, with safety resultsin both the Rollover and Switch Cohorts consistent with the safetyprofile observed in First-HD.

In the Rollover Cohort, 39 (52.0%) subject experienced AEs, with the AEsassessed as mild or moderate in intensity in 36 (92.3%) of these 39subjects. The most common AEs in the Rollover Cohort were fall (10subjects, [13%]), somnolence (6 [8%]), depression (6 [8%]), and insomnia(6 [8%]). A similar percentage of subjects in the Rollover Cohortexperienced AEs from Day 1 through Week 8 (45.3%) compared with Week 8through the visit cut-off date (43.2%). Five subjects had an AE that ledto a dose reduction or dose suspension. Three subjects experiencedserious AEs (anxiety, major depression, suicidal ideation, dehydration,encephalopathy, and depression suicidal), with one of these serious AEs(major depression) leading to study withdrawal. Three additionalsubjects withdrew from the study due to an AE (worsening chorea,suicidal ideation, and depression).

In the Switch Cohort, 21 (56.8%) subjects experienced at least one AE,with AEs assessed as mild to moderate in intensity in 20 (95.2%) of the21 subjects. The most common AEs in the Switch Cohort were somnolence (9subjects [24%]), anxiety (3 [8%]), and fall (3 [8%]). The majority ofthese common events occurred during the first 8 weeks of the study (22Switch subjects had reached Week 8 by the visit cut-off date). The mostcommon AEs occurred at similar rates from Day 1 through Week 1, Week 2through Week 4, and Week 5 through Week

8. There were no adverse events of chorea or worsening chorea during thereporting period, including the first week after the conversion fromtetrabenazine to deutetrabenazine. Two subjects experienced serious AEs(pneumonia and dehydration), no subjects withdrew from the study due toan AE, and four subjects had an AE that led to a dose reduction or dosesuspension.

There were no apparent increases in the overall incidence of AEs insubjects with impaired CYP2D6 metabolism (including subjects using astrong CYP2D6 inhibitor and CYP2D6 poor metabolizers).

Frequent treatment-emergent AEs, defined as events occurring in at least4% of subjects across all time periods in either cohort, are summarizedbelow in Table 21. The most common AEs during the Entire TreatmentPeriod in the Rollover Cohort were fall (10 subjects, [13.3%]),somnolence (6 [8.0%]), depression (8 [10.7%]), and insomnia (6 [8.0%]).The most common AEs during the Entire Treatment Period in the SwitchCohort were fall (3 subjects, [8.1%]), somnolence (9 [24.3%], but mostwere transient and did not require dose adjustment), depression (8[10.7%]), and anxiety (3 [8.1%]). The types of common adverse eventsobserved were consistent with those observed with deutetrabenazinetreatment in First-HD. Falls are difficult to assess in this studypopulation with chorea and HD; the majority of the falls were notconsidered to be related to study drug.

TABLE 21 TEAEs Occurring in at Least 4% of Subjects in Either CohortRollover Cohort Switch Cohort (N = 75) (N = 37) Event n (%) n (%) Fall10 (13.3) 3 (8.1) Depressiona  8 (10.7) 2 (5.4) Somnolence  6 (8.0) 9(24.3) Insomnia  6 (8.0) 1 (2.7) Diarrhoea  4 (5.3) 2 (5.4) Anxiety  3(4.0) 3 (8.1) Constipation  3 (4.0) 2 (5.4) Dry mouth  3 (4.0) 2 (5.4)Irritability  3 (4.0) 2 (5.4) Vomiting  3 (4.0) 1 (2.7) Fatigue  3 (4.0)1 (2.7) Sleep disorder  3 (4.0) 0 Nasopharyngitis  2 (2.7) 2 (5.4)Disorientation  0 2 (5.4)

Additional Safety Measures. Safety scales were incorporated into thestudy design to monitor for subclinical toxicity associated withdeutetrabenazine treatment. These included observed values and changesin the UHDRS, SDQ, UPDRS dysarthria question, Barnes Akathisia RatingScale (BARS), HADS, Epworth Sleepiness Scale (ESS), Columbia SuicideSeverity Rating Scale (C-SSRS), and Montreal Cognitive Assessment(MoCA©). The overall analysis of the safety scales showed no increasedrisk with deutetrabenazine treatment through Week 28 as of the visitcut-off date for this study. Eight Rollover patients had apparentdecline in two of four cognitive measures (MoCA and the verbal fluencytask) at Week 28. These changes were often associated with AEs (e.g.,somnolence, fatigue, urinary tract infection) and were typically notassociated with reduced performance on functional measures. Noclinically relevant changes in vital signs, ECGs, or clinical laboratoryassessments were observed during the study. Regarding body weight, frombaseline through Week 15, body weight increased in the Rollover cohortand changed minimally in the Switch Cohort. Following Week 15, there wasa trend toward weight loss at Week 28 in both cohorts (Rollover Cohort,1.4 kg; Switch cohort 1.9 kg), however the decrease in the number ofsubjects that reached the Week 28 milestone limits the interpretation ofthese results.

Taken together, the results of this study support deutetrabenazine as aneffective therapeutic option, with a favorable safety profile, fortreatment of chorea associated with HD. The results support the safetyof an overnight switch from TBZ to a predicted AUC-matched dose ofdeutetrabenazine, which can be achieved without a loss of choreacontrol.

Tardive Dyskinesia

An open-label, single-arm study in which male and female subjects withmoderate to severe drug-induced tardive dyskinesia (TD) was conducted toevaluate the safety and tolerability of long-term maintenance therapywith deutetrabenazine, and to evaluate the efficacy of long-termmaintenance therapy of deutetrabenazine to reduce the severity ofabnormal involuntary movements of TD.

Study Design. Inclusion criteria included: at least 18 years of age;successful completion of prior deutetrabenazine controlled study fortreatment of moderate to severe TD; history of using a dopamine receptorantagonist for at least 3 months (or 1 month in subjects 60 years of ageand older); clinical diagnosis of TD and has had symptoms for at least 3months; for subjects with underlying psychiatric illness:

-   -   psychiatrically stable and no change in psychoactive medications        for ≥30 days before screening (45 days for antidepressants);    -   subjects on long acting (depot) medications have been on stable        therapy (dose, frequency) for ≥3 months before Screening; and    -   subject has a mental health provider who is aware of the        subject's participation in the trial and does not anticipate any        changes to the subject's treatment regimen (drug, dose,        frequency) in the next 3 months;    -   history of being compliant with prescribed medications; able to        swallow study drug whole; lives in a stable environment, and has        adequate supervision when necessary to comply with all study        procedures, attend all study visits, and safely participate in        the trial; sufficient reading skills to comprehend the        subject-completed rating scales; female subjects of childbearing        potential agree to use one of the following acceptable methods        of contraception from screening through study completion if        sexually active:    -   IUD or intrauterine system in place for at least 3 months prior        to screening;    -   Subject or partner using barrier method with spermicide from        screening through study completion;    -   Partner has a documented vasectomy >6 months prior to        enrollment; or    -   Stable hormonal contraception (with approved oral, transdermal,        or depot regimen) for at least 3 months prior to screening,

Exclusion criteria included: subject has received tetrabenazine within 7days of baseline, or any of the following medications within 30 days ofBaseline: reserpine, α-methyl-p-tyrosine (AMPT), botulinum toxin (within3 months of Baseline), and medications with strong anticholinergicactivity (trihexyphenidyl, benztropine, orphenadrine, procyclidine, andbiperiden), metoclopramide, promethazine, prochlorperazine, stimulants(i.e., methylphenidate, amphetamine/dextroamphetamine,lisdexamphetamine, etc.), monoamine oxidase inhibitors, and (MAOIs),levodopa or dopamine agonists; subject has a neurological conditionother than TD that may interfere with assessing the severity ofdyskinesias; serious untreated or undertreated psychiatric illness atbaseline; active suicidal ideation at baseline; history of any of thefollowing within 6 months of Baseline: previous intent to act onsuicidal ideation with a specific plan (positive answer to question 5 onC-SSRS) irrespective of level of ambivalence at the time of suicidalthought, previous preparatory acts to commit suicide or suicidalbehavior, or previous actual, interrupted, or aborted suicide attempt;score ≥11 on the depression subscale of the Hospital Anxiety andDepression Scale (HADS) at baseline; subject is developmentally disabledor has evidence of dementia; subject has an unstable or serious medicalillness at baseline; history (within 3 months) or presence of violentbehavior; QTcF value >450 ms (males) or >460 ms (females), or >480 ms(with right bundle branch block [RBBB]) on 12-lead electrocardiogram(ECG) at baseline; evidence of hepatic impairment at Screening, asindicated by: aspartate transaminase (AST) or alanine aminotransferase(ALT) >2.5 times the upper limit of normal (ULN), alkaline phosphatase(ALP) or total bilirubin (TBil) >2 times the ULN (but subjects withGilbert's Syndrome are eligible to participate if approved by themedical monitor, and subjects with abnormalities in two or more of theseanalytes (AST, ALT, ALP, TBil) must be approved by the Medical Monitorto be enrolled), and prothrombin time >4 sec prolonged; positiveHepatitis B surface antigen (HBsAg); evidence of significant renalimpairment at Screening, indicated by a creatinine clearance <50 mL/min,as estimated by the Cockroft-Gault formula; known allergy totetrabenazine or to any of the components of deutetrabenazine; hasparticipated in an investigational drug or device trial (other thaneligible deutetrabenazine study) and received study drug within 30 days(or 5 drug half-lives) of baseline, whichever is longer; subject ispregnant or breast-feeding at baseline; and present use of illicit drugsat baseline.

Dose Regimen. Deutetrabenazine tablets were provided in dosage strengthsof 6, 9, 12, 15, and 18 mg. During dose adjustment/titration,deutetrabenazine was supplied in weekly blister cards. During long-termtreatment, deutetrabenazine will be supplied in 30-count bottles. Studydrug were administered as follows. All treatment regimens wereadministered twice daily (BID) with meals, approximately 10 hours apartduring the day. The starting dose was deutetrabenazine 12 mg/day (6 mgBID) regardless of previous treatment in the parent trial. Priortreatment assignment from the parent trial remained blinded. The maximumtotal daily dose of deutetrabenazine was 48 mg/day (24 mg BID) unlessthe subject is on a strong CYP2D6 inhibitor (paroxetine, fluoxetine, orbupropion), in which case the maximum total daily dose is 36 mg/day.Daily doses up to 36 mg/day were given as one tablet BID whereas dailydoses of 42 mg/day and 48 mg/day were given as two tablets BID. Duringthe titration period, the dose of deutetrabenazine should be increasedon a weekly basis in increments of 6 mg per day until 1) there wasadequate control of dyskinesia; 2) the subject experienced a protocoldefined clinically significant AE (defined as related to study drug andeither a) moderate or severe in intensity or b) meets the criteria for aSAE); or 3) the maximal allowable dose was reached. If a subjectexperienced a clinically significant AE attributable todeutetrabenazine, the Investigator determined if a dose reduction orsuspension was necessary.

Long-Term Treatment. For all subjects participating in the Long-TermTreatment Period, the dose of deutetrabenazine may be adjusted (upwardor downward) in increments of 6 mg per day, if necessary, to optimizedyskinesia control while minimizing AEs. However, such changes in dosemay not occur more frequently than once per week.

Titration Period (up to 6 weeks). Subjects who successfully completed aparent study were eligible to enroll into this study after a 1-weekwashout period and the final evaluation. As subjects had discontinuedstudy drug or placebo for 1 week, they underwent deutetrabenazine dosetitration in this study. During titration, the investigator, inconsultation with the subject determined when an adequate level ofdyskinesia control had been achieved. The dose of deutetrabenazine wasadjusted (upward or downward) in increments of 6 mg per day up to onceper week, until adequate control of dyskinesia was achieved, aclinically significant adverse event related to study drug (either a)moderate or severe in intensity or b) a serious adverse event) occurred,or the maximal allowable dose is reached. If a subject experienced aclinically significant AE attributable to deutetrabenazine, theinvestigator determined if a dose reduction or suspension was necessary.Subjects had a telephone contact at Week 1 and a clinic visit at Week 2,to evaluate safety and establish a dose of study drug that adequatelycontrolled dyskinesia and was well tolerated. Although subjects enteredthe long-term treatment period after Week 2, titration continued throughWeek 6 to optimize dose.

Long-Term Treatment Period (up to 52 weeks). During long-term treatment,subjects will continue titration through Week 6. During this period, allsubjects will be contacted by telephone at Week 3 (the first week of theLong-Term Treatment Period) and Week 5 and will return to the clinic atWeeks 4, 6, 15, 28, 41, and 54 for evaluation of safety and dyskinesiacontrol. Subjects who have not achieved a dose level that adequatelycontrols dyskinesia and is well tolerated by the Week 6 visit shouldhave unscheduled visits or telephone contacts to further adjust theirdose upward or downward. Interactions with the clinical site for doseadjustment should alternate between telephone contacts and clinicvisits. During long-term treatment, further dose adjustments ofdeutetrabenazine may be made, if necessary, but not more often thanweekly and only in increments of 6 mg per day. Dose adjustments shouldbe based on all available information, including the subject's andcaregiver's (if appropriate) reports of AEs and dyskinesia control, aswell as information from rating scales and safety evaluations, whenavailable.

Post-Treatment Safety Follow Up. All subjects will discontinue studydrug at the Week 54 visit and return for their final clinic visit atWeek 55 for evaluation of safety, dyskinesia control, and motorfunction. During this 1-week washout period, subjects should not takeprohibited concomitant medications. Subjects will also have a follow-uptelephone contact at Week 58, four weeks after their last dose of studydrug, to evaluate AEs and concomitant medication usage.

Safety Endpoints. Safety and tolerability will be assessed throughoutthe study by monitoring the following parameters: adverse events (AEs),clinical laboratory tests, physical examination, vital signs, 12-leadECGs, Unified Parkinson's Disease Rating Scale (UPDRS) Part III (motorexamination), Barnes Akathisia Rating Scale (BARS), Hospital Anxiety andDepression Scale (HADS), Columbia Suicide Severity Rating Scale(C-SSRS), Epworth Sleepiness Scale (ESS), and Montreal CognitiveAssessment (MoCA©).

Efficacy Endpoints. The following measures were or will be used toassess efficacy: change in Abnormal Involuntary Movement Scale (AIMS)score (items 1 through 7) from baseline to end of long-term therapy(Week 54) as assessed by blinded central video rating; proportion ofsubjects who are a treatment success at the end of long-term therapy(Week 54), based on the Clinical Global Impression of Change (CGIC) (inwhich a treatment success is defined as Much or Very Much Improved);change in the modified Craniocervical Dystonia (CDQ-24) score frombaseline of this study to the end of long-term therapy (Week 54);proportion of subjects who have a 50% or greater reduction in AIMS scorefrom baseline of this study to the end of long term therapy (Week 54);proportion of subjects who are a treatment success at the end oflong-term therapy (Week 54), based on the Patient Global Impression ofChange (PGIC) (in which a treatment success is defined as Much or VeryMuch Improved); percent change in AIMS score from Baseline of this studyto the end of long term therapy (Week 54); and based on the change inAIMS score from baseline of this study to the end of long-term therapy(Week 54), as assessed by blinded central video rating, the cumulativeproportion of responders ranging from a 10% improvement from baseline toa 90% improvement from baseline in steps of 10 percentage points.

Results. Results are given in FIG. 9, which shows that by Week 6 of thestudy, over 50% of subjects were much or very much improved according toPGIC and CGIC.

ARM-TD

An additional clinical study, Aim to Reduce Movements in TardiveDyskinesia (ARM-TD) was designed and conducted to evaluate the efficacyof SD-809 (deutetrabenazine) in the treatment of moderate to severetardive dyskinesia. The ARM-TD study was a 1:1 randomized, double-blind,placebo-controlled, parallel-group study of 117 patients globally (with104 patients completing the trial) with moderate to severe tardivedyskinesia.

Subjects were screened for inclusion in the study as follows. Inclusioncriteria included: between 18 and 75 years of age, inclusive; history ofusing a dopamine receptor antagonist for at least 3 months (or 1 monthin subjects 60 years of age and older); clinical diagnosis of TD, andhas had symptoms for at least 3 months prior to Screening; TD symptomsare bothersome to the subject or cause functional impairment; atScreening and Baseline visits, the subject has moderate or severeabnormal movements as judged by the Investigator based on Item 8 of theAIMS and a total motor AIMS score of ≥6 (based on Items 1 through 7) asassessed by the Principal Investigator; for subjects with underlyingpsychiatric illness, subject is psychiatrically stable and has had nochange in psychoactive medications (including, but not limited toneuroleptics, benzodiazepines, anticonvulsants, and mood stabilizers)for ≥30 days before Screening (45 days for antidepressants); subjects onlong-acting (depot) medications have been on stable therapy (dose,frequency) for ≥3 months before Screening; and subject has a mentalhealth provider who is aware of the subject's participation in thetrial, and does not anticipate any changes to the subject's treatmentregimen (drug, dose, frequency) in the next 3 months; history of beingcompliant with prescribed medications; able to swallow study drug whole;written, informed consent; subject has good general health, lives in astable environment, is expected to complete all study assessments, andhas adequate supervision when necessary to comply with all studyprocedures, attend all study visits and safely participate in the trial;sufficient reading skills to comprehend the subject-completed ratingscales; and, if female and of childbearing potential, agree to useacceptable methods of contraception from Screening through studycompletion if sexually active.

Exclusion criteria included: score ≥11 on the depression subscale of theHospital Anxiety and Depression Scale (HADS) at Screening or Baseline;developmentally disabled or has evidence of dementia; unstable orserious medical illness at Screening or Baseline; history (within 3months) or presence of violent behavior; QTcF value >450 ms (males)or >460 ms (females), or >480 ms (with right bundle branch block [RBBB])on 12-lead ECG at Screening; evidence of hepatic impairment atScreening, as indicated by: AST or ALT >2.5 times the upper limit ofnormal (ULN), or ALP or total bilirubin >2 times the ULN (whereinabnormalities in two or more of these AST, ALT, ALP, TBil must beapproved by the Medical Monitor to be enrolled, but subjects withGilbert's Syndrome eligible if approved by the Medical Monitor), orProthrombin time >4 seconds prolonged, or positive HBsAg; evidence ofsignificant renal impairment at Screening, indicated by a creatinineclearance <50 mL/min, as estimated by the Cockroft-Gault formula; knownallergy to tetrabenazine or to any of the components ofdeutetrabenazine; subject has participated in an investigational drug ordevice trial and received study drug within 30 days (or 5 drughalf-lives) of Screening, whichever is longer; pregnant orbreast-feeding at Screening or Baseline; acknowledged present use ofillicit drugs at Screening; history of alcohol or substance abuse in theprevious 12 months, as defined in the DSM-V, or subject is unable torefrain from substance abuse throughout the study; and positive urinedrug screen (for amphetamines, barbiturates, benzodiazepine,phencyclidine, cocaine, or opiates) at Screening or Baseline, except ifsubject is receiving a stable dose of a benzodiazepine.

Dosing. Enrolled patients received either deutetrabenazine or placebo,which was titrated from a starting dose of 6 mg of deutetrabenazine(which, as in previous studies, provides an AUC of total (α+β)-HTBZ thatis comparable to 12.5 mg of tetrabenazine) to optimal dosage between 12and 48 mg/day over the course of six weeks, in increments of 6 mg/dayper week. Drug was then administered at that dose for another six weeksfor a total treatment of 12 weeks, followed by a 1-week washout period.Randomization to each group was 1:1 and was stratified by baseline useof dopamine receptor antagonists (currently taking versus not).Deutetrabenazine tablets or placebo, were supplied as 6, 9, 12, 15, and18 mg tablets and administered BID with meals in the morning and evening(recommended 10 hours apart; minimum 6 hours apart). Dose suspensions ofup to one week were permitted if the subject experienced a clinicallysignificant adverse event.

Study Objectives and Endpoints. The objectives of the study was toevaluate the efficacy of SD-809 in reducing the severity of abnormalinvoluntary movements associated with tardive dyskinesia and the safetyand tolerability of titration and maintenance therapy withdeutetrabenazine in subjects with drug-induced tardive dyskinesia. Theprimary efficacy endpoint is the change in AIMS score (Items 1 through7) from baseline to Week 12, as assessed by blinded central videorating. Baseline AIMS score is defined for each subject as the Day 0assessment. The AIMS is composed of 12 clinician-administered and scoreditems. Items 1-10 are rated on a 5-point, anchored scale and consist ofthe following:

-   -   Items 1-4 assess orofacial movements;    -   Items 5-7 deal with extremity and truncal dyskinesia;    -   Items 8-10 deal with global severity as judged by the examiner,        and the patient's awareness of the movements and the distress        associated with them; and    -   Items 11-12 are yes/no questions concerning problems associated        with teeth and/or dentures, as such problems can be mistaken for        dyskinesia.

A total score from items 1 through 7 (orofacial, extremity and truncalmovements) can be calculated and represent observed movements, withhigher scores indicative of more severe dyskinesia. Item 8 can be usedas an overall severity index; items 9 and 10 provide additionalinformation with regard to patient incapacitation and awareness; anditems 11 and 12 provide information that may be useful in determininglip, jaw, and tongue movements.

The key secondary endpoints are: 1) the proportion of subjects who are atreatment success at Week 12, based on the Clinical Global Impression ofChange (CGIC); 2) the proportion of subjects who are a treatment successat Week 12, based on the Patient Global Impression of Change (PGIC); and3) the change in the modified Craniocervical Dystonia Questionnaire(CDQ-24) from baseline to Week 12. As with previous studies, PGIC/CGICtreatment success may be defined as Much or Very Much Improved on a7-point Likert Scale, ranging from very much worse to very much improvedat Week 12. The CDQ-24 is a disease-specific quality of lifequestionnaire developed for use in patients with craniocervicaldystonia, including both cervical dystonia (CD) and blepharospasm (BPS).The CDQ-24 was selected for use in the present study because it includesdomains which are relevant not only to CD and BPS, but to TD, such asstigma, emotional well-being, pain, activities of daily living, andsocial/family life. For the present study, the CDQ-24 has been modifiedsuch that the questions focus more directly on the impact of TD (asopposed to CD/BPS) on quality of life.

Additional secondary endpoints included 1) the percent change in AIMSscore (central rating) from baseline to Week 12; 2) based on the changein AIMS score (central rating) from baseline to Week 12, the cumulativeproportion of responders for responder levels ranging from a 10%improvement from baseline to a 90% improvement from baseline in steps of10 percentage points; and 3) Change in AIMS score (Items 1 through 7)from baseline to Week 12, as assessed by the local rater, whereinbaseline AIMS score is defined for each subject as the Day 0 assessment.

Finally, at each clinical site, an Investigator experienced in assessingmovement disorders, was responsible for confirming the diagnosis of TD,performing all clinical assessments, and making decisions aboutadjusting the dose of study drug. Safety was also monitored via adverseevents reporting and other measures, including but not limited to theUPDRS, BARS, HADS, C-SSRS, ESS, and MoCA.

Measurements and Statistics. Digital video recordings of AIMSassessments made at all clinic visits (at Screening, Baseline, Weeks 2,4, 6, 9, and 12) were rated by pairs of central raters who were expertsin movement disorders and were blinded to treatment arm, sequence ofvideo, and the investigator AIMS score. Analysis was carried out using alinear mixed model for repeated measurements (MMRM) with the change inthe AIMS score as the dependent variable. The model included fixedeffects for treatment group, time point (five levels: Weeks 2, 4, 6, 9,and 12), the treatment group by time point interaction, and therandomization stratification variable. The unstructured covariance modelwas used and the primary analysis compared the deutetrabenazine andplacebo groups at Week 12 using a two-sided test at the 5% level ofsignificance.

Efficacy Results. Top-line data showed that the study met its primaryendpoint. Patients taking deutetrabenazine achieved an improvement of3.0 points on the AIMS score from baseline to end of therapy compared to1.6 points in placebo (p=0.0188) for a clinically meaningful effect.Additionally, secondary endpoints numerically favored deutetrabenazine.Results are given in Table 22,

TABLE 22 DTBZ Placebo Treatment (N =56) (N =57) Difference AIMS Change(LS Mean) −3 −1.6 −1.4 (p-value 0.0188) PGIC Treatment Success 42.90%29.80% 13.00% N (%) CGIC Treatment Success 48.20% 40.40% 7.90% (%)Change from baseline −11.1 −8.3 −2.7 mCDQ-24*

Safety Results. The study also showed a favorable safety andtolerability profile for deutetrabenazine, including low rates ofdepression, somnolence, insomnia and akathisia. Fewer patients takingdeutetrabenazine than placebo experienced serious adverse events (SAEs)(4 patients [6.9%] in deutetrabenazine versus 6 [10.2%] in placebo; noneof the SAEs were treatment related) or experienced adverse eventsleading to discontinuation (1 patient [1.7%] versus 2 patients [3.4%]).Neuropsychiatric adverse events in this patient population wereinfrequently associated with SD-809 treatment compared to placebo, andincluded somnolence/sedation (9 [15.5%] versus 6 [10.2%]), insomnia (4[6.9%] versus 1 [1.7%]), akathisia (3 [5.2%] versus 0 [0.0%])(Depression/depressed mood was reported by one patient in each treatmentgroup, and suicidal ideation was reported by one patient in the placebogroup versus none in the SD-809 group. Three patients discontinued fromthe study for adverse events (1 in deutetrabenazine group vs. 2 inplacebo group). For all other side effects reported in the study, ratesin the deutetrabenazine group were similar or lower than the placebogroup. Results are shown below in Table 23, which includes adverseevents observed in 3 or more subjects.

TABLE 23 DTBZ Placebo (n = 58) (n = 59) Any TEAEs (Treatment-Emergent 41(70.7%) 36 (61.0%) Adverse Events) Serious TEAEs  4 (6.9%)  6 (10.2%)TEAEs Resulting in Study Withdrawal  1(1.7%)  2 (3.4%) Nervous systemSomnolence/  9 (15.5%)  6 (10.2%) disorders sedation Headache  4 (6.9%) 6 (10.2%) Dizziness  2 (3.4%)  3 (5.1%) Akathisia  3 (5.2%)  0 (0.0%)Psychiatric disorders Anxiety  3 (5.2%)  4 (6.8%) Insomnia  4 (6.9%)  1(1.7%) Gastrointestinal Dry mouth  2 (3.4%)  6 (10.2%) disordersDiarrhea  3 (5.2%)  3 (5.1%) Constipation  2 (3.4%)  2 (3.4%) Nausea  2(3.4%)  2 (3.4%) Vomiting  1 (1.7%)  3 (5.1%) General disorders Fatigue 4 (6.9%)  5 (8.5%) Chest pain  1 (1.7%)  2 (3.4%) Infections and Upperrespiratory  2 (3.4%)  4 (6.8%) infestations tract infection    Nasopharyngitis  2 (3.4%)  1 (1.7%) Pneumonia  1 (1.7%)  2 (3.4%)

Based on the studies disclosed herein, it is expected thatdeutetrabenazine, other deuterium substituted tetrabenazines andvalbenazine will be efficacious in the treatment of tardive dyskinesiaand other movement disorders and symptoms, such as dyskinesiasgenerally, dystonia, ballismus, akinesia, and parkinsonism, and that thedosing regimens and methods disclosed herein will yield significantpatient benefits.

Tourette Syndrome

Tourette syndrome (TS) is a neurological disorder characterized byrepetitive, stereotyped, involuntary movements and vocalizations calledtics, which per DSM-V criteria first presents in childhood, before 18years of age. Several studies have been or could be used to demonstratethe efficacy and tolerability of deutetrabenazine in the reduction ofsymptoms associated with TS, including motor and phonic tics.

Open-Label Pilot Study of Safety and Efficacy in TS Patients

An open-label, pilot study was undertaken 1) to evaluate the safety andtolerability of treatment with deutetrabenazine, and 2) to evaluate theefficacy of deutetrabenazine to suppress the motor and phonic tics ofTS.

Study Design. Inclusion criteria (at screening, unless otherwiseindicated) included: 12 to 18 years of age, inclusive; DSM-V diagnosisof TS and has manifested motor and phonic tics within 3 months beforescreening; total tic score of 19 or higher on the YGTSS; TS-CGI score of4 or higher (consistent with moderately ill); tic severity and frequencyhas been stable for at least 2 weeks; able to swallow study medicationwhole; willing to adhere to medication regimen and to comply with allprocedures; in good general health, as indicated by medical andpsychiatric history as well as physical and neurological examination;written, informed consent (subject and parent/guardian); and femalesubjects of childbearing potential agree to use an acceptable method ofcontraception through study completion, including abstinence, IUD orintrauterine system in place for at least 3 months prior; subject orpartner using barrier method (e.g., condom, diaphragm, or cervical cap)with spermicide; partner has a documented vasectomy >6 months prior toenrollment; stable hormonal contraception (with approved oral,transdermal, or depot regimen) for at least 3 months prior.

Exclusion criteria (at screening or baseline, unless otherwiseindicated) included: serious untreated or undertreated psychiatricillness, such as depression, schizophrenia, or bipolar disorder (butsubjects receiving antidepressant therapy may be enrolled if on a stabledose for at least 8 weeks before); history of suicidal thoughts orbehavior, including previous intent to act on suicidal ideation with aspecific plan (positive answer to question 5 on the Columbia SuicideSeverity Rating Scale [C-SSRS]) irrespective of level of ambivalence atthe time of suicidal thought, previous preparatory acts or behavior, orprevious actual, interrupted, or aborted suicide attempt; subject hasreceived any of the following concomitant medications within 14 daysprior to screening or baseline: tetrabenazine, neuroleptics (oral ordepot, typical and atypical; depot\within 3 months of screening),guanfacine or clonidine (within 7 days of screening or baseline),benzodiazepines such as clonazepam, topiramate, metoclopramide,monoamine oxidase inhibitors (MAOIs), levodopa or dopamine agonists,reserpine (within 21 days of screening or baseline), botulinum toxin(within 3 months of screening or baseline); subject is being treatedwith deep brain stimulation for control of tics; below-averageintelligence or mental abilities, in the opinion of the Investigator;progressive or degenerative neurological disorder or a structuraldisorder of the brain; subject receiving more than one agent for thetreatment of each co-morbid behavioral symptom; subject requirestreatment with drugs known to prolong the QT interval (but citalopramand escitalopram allowed when administered according to approvedlabeling); QTcF value >440 ms on 12-lead electrocardiogram (ECG); knownallergy to any of the components of study medication; participation inan investigational drug or device trial within 30 days (or 5 drughalf-lives) of screening, whichever is longer; pregnant orbreast-feeding; present use of illicit drugs; and history of alcohol orsubstance abuse in the previous 12 months, as defined in the DSM-V, orunable to refrain from substance abuse throughout the study.

Subjects completing the trial received treatment with study drug for atotal of 8 weeks and had safety follow-up 4 weeks after treatment.Throughout the study, an independent rater assessed tic severity withthe Yale Global Tic Severity Scale (YGTSS) and tic impact with theTS-Clinical Global Impression (TS-CGI) scale. The independent rater willnot have knowledge of the subject's clinical care, including medicationsor reports of adverse events (AEs).

Dose regimen. Study drug was available in five dose strengths: 6, 9, 12,15, and 18 mg, all of which were identical in size, shape, and color(white). Subjects who qualified for the study were assigned to treatmentwith deutetrabenazine and were titrated over 6 weeks to a dose level ofstudy drug that adequately suppressed tics and was well tolerated (i.e.,optimal dose). Subjects then maintained that dose level for the durationof the treatment period. Subjects who were receiving CBIT (ComprehensiveBehavioral Intervention for Tics) therapy were permitted to participateas long as therapy had been stable/ongoing for at least 4 weeks beforeScreening and was expected to be stable for the duration of the trial.Study drug was dosed as follows. All treatment doses were administeredwith meals. A daily dose of 6 mg was given once a day in the morning,and daily doses of 12 mg and higher were administered twice daily individed doses, approximately 10 hours apart during the day. The startingdose was deutetrabenazine 6 mg in the AM. The dose of study drug wasoptionally adjusted weekly in increments of 6 mg/day during thetitration period to identify a dose level that suppressed tics and waswell tolerated. Dose reductions were in increments of 6 mg/day. In thisstudy, the maximum total daily dose of deutetrabenazine at the Week 5visit or later was 36 mg (18 mg twice daily [BID]).

Screening/Baseline visit. After informed consent/written assent wasobtained, subjects who met selection criteria had a comprehensiveevaluation including physical and neurological examination. Subjectsthen underwent a baseline assessment of tic severity (performed by anindependent rater) and co-morbid illnesses. Following this evaluation,subjects continuing to meet selection criteria were provided withdeutetrabenazine and were instructed to start treatment on Day 1, theday after the baseline visit.

Titration period (6 weeks). Subjects and their parent/guardianinteracted weekly with the clinical research staff, either by telephonecontact or clinic visit, through the sixth week of the titration period,in order to evaluate safety and establish a dose of deutetrabenazinethat adequately suppressed tics and was well tolerated. Safetyevaluations during titration included assessment of vital signs,monitoring for adverse events, and rating scales for depression andsuicidal ideation and behavior. In-person study visits were scheduled atWeeks 2 and 4 after initiating therapy and telephone contacts werescheduled for Weeks 1, 3, 5, and 6 after initiating therapy in order toassess tic suppression and adverse events. The YGTSS and TS-CGI wereassessed by an independent rater. The Investigator, in consultation withthe subject and parent/guardian, determined when an adequate level oftic suppression had been achieved. The dose of deutetrabenazine wasincreased on a weekly basis until there was adequate suppression oftics, the subject experienced a protocol-defined “clinicallysignificant” AE (defined as an AE that is related to study medicationand either (1) moderate or severe in intensity or (2) meets the criteriafor a serious adverse event [SAE]), or the maximal allowable dose wasreached. Although dose adjustments could made up to and including theWeek 5 phone call, if a stable dose was reached before then, the subjectcontinued on that dose for the remainder of the titration period andthroughout maintenance dosing. Once adequate suppression of tics hadbeen achieved, the dose of study drug was not increased further. If asubject experienced a “clinically significant” AE that was attributed tostudy drug, the Investigator used his or her judgment to determine if adose reduction or suspension was necessary. Dose adjustments were to bemade based on all available information, including the subject andparent/guardian reports of AEs and tic suppression, the clinicalassessment of safety and efficacy by the Investigator, as well asinformation from rating scales. At the end of the titration period, thesubject's dose was established for the maintenance period.

Maintenance period (2 weeks). Subjects continued to receive theirmaintenance dose over the next 2 weeks, although dose reductions for AEswere allowed. Subjects returned to the clinic at Week 8 for a completeevaluation, including physical and neurological examination andperformance of all rating scales, including the YGTSS and TS-CGI, whichwere assessed by an independent rater. Subjects discontinued study drugat the Week 8 visit.

Follow-up (4 weeks). Subjects returned 1 week after the Week 8 visit forevaluation of safety and tic suppression. Subjects also had a follow-uptelephone contact 4 weeks after their last dose of study drug. Subjectswho completed the study were potentially eligible to participate in along-term safety study if such a study were conducted.

Pharmacokinetics. A PK substudy was conducted to evaluate the PK ofdeutetrabenazine and its metabolites in up to 9 of the 21 enrolledsubjects. Subjects in the PK substudy underwent sequential PK bloodsampling over the course of 6 hours postdose at the Week 8 visit. Forthe subjects not participating in the PK substudy, a single PK samplewas obtained at Week 8 at the time of the blood draw for clinicallaboratory tests.

Safety Endpoints. Safety and tolerability were assessed throughout thestudy by monitoring the following parameters: adverse events (AEs),clinical laboratory tests, physical examination, vital signs, 12-leadECGs, Columbia Suicide Severity Rating Scale (C-SSRS), Beck DepressionInventory, Second Version (BDI-II), and the Children's Yale-BrownObsessive-Compulsive Scale (CY-BOCS).

Efficacy Endpoints. The following measures were used to assess efficacy:Yale Global Tic Severity Scale (YGTSS), Total Tic Severity Score (TTS)of the YGTSS, Global Severity Score (GSS) of the YGTSS, TouretteSyndrome Clinical Global Impression (TS-CGI), and Tourette SyndromePatient Global Impression of Change (TS-PGIC).

Results. Initial results indicate that deutetrabenazine is efficaciousin the treatment of tics associated with Tourette syndrome. A consistenttrend of improvement was observed in motor, vocal, total tic severity,and Yale global total tic severity from baseline through the end of theeight-week treatment phase. This culminated in a mean change of −10.4units in total tic severity. Additionally, discontinuation in treatmentafter week 8 led to a slight increase in tics. Results are given belowin Table 24; ND indicates no data.

TABLE 24 Overall (N = 23) Visit MTSS VTSS TTS Impairment GSS B* n 23 2323 23 23 Mean 17.4 14.2 31.6 34.3 66.0 (SD) (3.95) (5.66) (7.92) (9.45)(15.99) Median 18 15 31 30 68 Min, Max 10, 24 0, 22 19, 46 20, 50 39, 96Wk 2 n 21 21 21 ND 21 Mean 15.9 13.5 29.4 ND 59.4 (SD) (5.06) (5.64)(9.81) (19.45) Median 16 14 28 ND 57 Min, Max 0, 24 4, 22 4, 46 ND 4, 96Δ B- n 21 21 21 ND 21 Wk 2 Mean −1.9 −1.0 −2.9 ND −7.7 (SD) (2.67)(3.29) (5.37) (12.25) Median 0 0 0 ND 0 Min, Max −10, 0 −11, 4 −21, 4 ND−41, 12 Wk 4 n 21 21 21 ND 21 Mean 14.2 12.1 26.3 ND 51.1 (SD) (6.30)(6.60) (11.91) (22.64) Median 14 12 27 ND 51 Min, Max 0, 25 0, 25 0, 50ND 0, 100 Δ B- n 21 21 21 ND 21 Wk 24 Mean −3.5 −2.5 −6.0 ND −16.0 (SD)(4.32) (4.55) (8.18) (18.84) Median −2 0 −3 ND −12 Min, Max −15, 2 −12,4 −25, 4 ND −55, 4 Wk 8 n 23 23 23 21 23 Mean 12.0 9.2 21.2 22.9 45.1(SD) (5.35) (6.64) (10.95) (11.46) (21.71) Median 11 9 23 20 47 Min, Max0, 24 0, 24 0, 48 0-50 0, 98 Δ B- n 23 23 23 21 23 Wk 28 Mean −5.3 −5.0−10.4 −11.9 −20.8 (SD) (4.98) (4.41) (8.83) (9.28) (17.61) Median −4 −4−10 −10 −16 Min, Max −15, 6 −14, 2 −25, 5 −30-0 −50, 15 Wk 9 n 18 18 18ND 18 Mean 13.9 11.7 25.6 ND 51.7 (SD) (4.94) (7.30) (11.06) (22.98)Median 14.5 10.5 26 ND 51 Min, Max 5, 25 0, 25 10, 50 ND 14, 100 Δ B- n18 18 18 ND 18 Wk 9 Mean −3.4 −2.9 −6.3 ND −14.7 (SD) (3.15) (3.80)(6.49) (15.50) Median −3 −2.5 −5 ND −10.5 Min, Max −11, 1 −11, 3 −22, 4ND −45, 4 *B = baseline; Wk = week

Additionally, preliminary results indicate improvements in several otherrelevant measures. In PGIC, a mean improvement of 1.8 points wasobserved (on the 7-point scale above where 1=minimally improved, 2=muchimproved, 3=very much improved), suggesting patients are generallyimproved after 8 weeks of treatment (about 75% much or very muchimproved). In TS-CGI, mean improvement from a baseline of 4.7 to 3.7 atWeek 8 was observed (on a 7 point scale where lower is better). Finally,the adverse event profile appeared generally consistent with previousstudies.

It is expected that deutetrabenazine, other deuterium substitutedtetrabenazines and valbenazine will be efficacious in the treatment ofTourette syndrome and other movement disorders and symptoms, such astics, stereotypy, akathisia, dyskinesia, and restless legs syndrome, andthat the dosing regimens and methods disclosed herein will yieldsignificant patient benefits.

Twelve-Week Randomized Phase 2/3 Study of Safety and Efficacy in TSPatients

Purpose. The primary objective of this study is to evaluate the efficacyof deutetrabenazine to reduce motor and phonic tics associated with TS;the secondary objective of this study is to evaluate the safety andtolerability of titration and maintenance therapy with deutetrabenazine.

Study Design. This is a Phase 2/3, randomized, double-blind,placebo-controlled, parallel group study in which patients with ticsassociated with TS will be invited to participate. The study willinclude male and female patients between 6 and 16 years of age(inclusive) with a tic associated with Tourette syndrome (TS). Patientswill be randomized and stratified by age at baseline [6 to 11 years, 12to 16 years]). The dose of study drug for each patient will be titratedto an optimal level followed by maintenance therapy at that dose. Theoverall treatment period will be 12 weeks in duration. The titrationperiod will be 7 weeks, and the maintenance period will be 5 weeks,which will be followed by a washout period of 1 week. Patients

Inclusion criteria. Patients may be enrolled in the study if they meetall of the following criteria: 6 to 16 years of age, inclusive, atbaseline; weight of at least 44 pounds (20 kg) at baseline; meets theDiagnostic and Statistical Manual of Mental Disorders, Fifth Edition(DSM-V) diagnostic criteria for TS and, in the opinion of theinvestigator, patient, and caregiver/adult, the patient's active ticsare causing distress or impairment; TTS of 20 or higher on the YGTSS atscreening and baseline; able to swallow study medication whole; patientand caregiver/adult are willing to adhere to the medication regimen andto comply with all study procedures; good general health, as indicatedby medical and psychiatric history as well as physical and neurologicalexamination; ability to understand the nature of the study and itsprocedures, and expected to complete the study as designed (ininvestigator's opinion); written informed consent; women/girls ofchildbearing potential (not surgically sterile (≥3 months)—via tuballigation, hysterectomy, oophorectomy—or congenitally sterile) whose malepartners are of childbearing potential must use contraception for theduration of the study and for 30 days after discontinuation of studydrug (acceptable methods of contraception are those with a failure rateof less than 1% per year, e.g., IUD, oral, implanted, transdermal, orinjected hormonal contraceptive, barrier method with spermicide, andpartner vasectomy.

Exclusion Criteria. Patients will not be enrolled in this study if theymeet any of the following criteria: neurologic disorder other than TSthat could obscure the evaluation of tics; patient's predominantmovement disorder is stereotypy (coordinated movements that repeatcontinually and identically) associated with Autism Spectrum Disorder;confirmed diagnosis of bipolar disorder, schizophrenia, or anotherpsychotic disorder; clinically significant depression at screening orbaseline (but patients receiving antidepressant therapy may be enrolledif on a stable dose for at least 6 weeks before screening (see listbelow for prohibited antidepressants); history of suicidal intent orrelated behaviors within 2 years of screening: previous intent to act onsuicidal ideation with a specific plan, irrespective of level ofambivalence, at the time of suicidal thought; previous suicidalpreparatory acts or behavior; history of a previous actual, interrupted,or aborted suicide attempt; a first-degree relative who has completedsuicide; clinically significant OCD at baseline that, in the opinion ofthe investigator, is the primary cause of impairment; patient hasreceived CBIT for TS or CBT for OCD within 4 weeks of screening; patienthas received any of the following concomitant medications for ticswithin the specified exclusionary windows of screening:

-   -   Within 3 months: depot neuroleptics, botulinum toxin, or        tetrabenazine;    -   Within 21 days: reserpine;    -   Within 14 days: monoamine oxidase inhibitors, neuroleptics        (oral), typical and atypical antipsychotics, metoclopramide,        levodopa, and dopamine agonists (note: use of benzodiazepines is        allowed if primary use is not for tics and dosing has been        stable for at least 4 weeks before screening; use of topiramate        (up to 200 mg/day) is allowed if dosing has been stable for at        least 4 weeks before screening; and use of guanfacine or        clonidine is allowed if dosing has been stable for at least 4        weeks before screening);        treatment with deep brain stimulation, or transmagnetic        stimulation or transcranial direct current stimulation for        reduction of tics within 4 weeks of the screening visit; an        unstable or serious medical illness at screening or baseline;        patient requires treatment with drugs known to prolong the QT        interval (list below); QTcF interval value >440 msec on 12-lead        ECG at screening; evidence of hepatic impairment (as indicated        by AST or ALT>2.5×the upper limit of the normal range (ULN) at        screening or ALP or total bilirubin (Tbil)>2×ULN at screening,        though patients with Gilbert's Syndrome and patients with        abnormalities in 2 or more of AST, ALT, ALP, and Tbil are        eligible to participate if approved by the medical monitor;        evidence of clinically significant renal impairment, indicated        by a serum creatinine>1.5×ULN at screening; known allergy to any        of the components of the study drug product; patient has        participated in an investigational drug or device trial and        received study drug/intervention within 30 days or 5 drug        half-lives of baseline, whichever is longer; pregnant or        breastfeeding; history of or acknowledged alcohol or substance        abuse in the previous 12 months, as defined in the DSM-V;        positive urine drug screen test result or is unable to refrain        from substance abuse throughout the study; and a DSM-V diagnosis        based on the MINI Kid Inventory modules performed at screening        that, in the opinion of the investigator, makes the patient        unsuitable for the study.

Prohibited drugs include: azithromycin, chloroquine/Mefloquine,clarithromycina, domperidone, droperidol, erythromycina, moxifloxacin,sevoflurane, probucol, sparfloxacin, chlorpromazine, aripiprazole,haloperidol, asenapine maleate, loxapine, clozapine, molindone,iloperidone, perphenazine, lurasidone, pimozide, olanzapine,prochlorperazine, olanzapine/fluoxetine, thioridazine paliperidone,thiothixene, quetiapine, trifluoperazine, risperidone,promethazine-containing compounds, ziprasidone, and tiapride.

Efficacy Endpoints. The study's primary efficacy endpoint will be thechange in the Total Tic Score (TTS) of the Yale Global Tic SeverityScale (YGTSS) from baseline to week 12, with a goal of reducing motorand phonic/vocal tics. Secondary efficacy endpoints will be changes inthe Tourette Syndrome-Clinical Global Impression (TS-CGI) score,Tourette Syndrome-Patient Global Impression of Severity (TS-PGIS) score,and the Gilles de la Tourette Syndrome—Quality of Life (GTS-QOL)physical/activities of daily living (ADL) subscale, all from baseline toweek 12.

Safety Endpoints. Safety endpoints will be: incidence of adverse events;observed values and changes from baseline in vital signs; observedvalues and change from baseline in the Children's Depression Inventory 2(CDI-2; Parent and Self-report versions); observed values in thechildren's Columbia Suicide Severity Rating Scale (C-SSRS); observedvalues in electrocardiogram (ECG) parameters and shifts from screeningfor clinically significant abnormal findings; and observed values andchanges from screening in clinical laboratory parameters (hematology,chemistry, and urinalysis).

Titration Period (7 weeks). Patients who remain eligible forparticipation in the study will be randomized at the baseline visit(day 1) and that evening (ie, after the study visit) will receive 6 mgof blinded study drug with food.

The dose of the study drug will be increased until 1) there is optimalreduction of tics, as determined by the investigator, in consultationwith the patient and caregiver/adult; 2) the dose is not tolerable.

Maintenance Period. At the end of the titration period, the patient'sdose will be established for the maintenance period. Patients willcontinue to receive their maintenance dose over the next 5 weeks,although dose reductions for adverse events are allowed. Patients willreturn to the clinic at weeks 9 and 12 for assessments of safety andefficacy. At week 12, patients will undergo a complete evaluation,including safety and efficacy measures.

Washout Period. All patients will discontinue study drug at the week 12visit and will return 1 week later for evaluation of safety and ticreduction (week 13).

Dose regimen. As discussed above, study drug will be administered asoral tablets at a starting dose of 6 mg once daily and titrated. Tabletsof deutetrabenazine will be available in the following dose strengths:6, 9, 12, 15, and 18 mg, distinguishable by imprint and color.Instruction will be provided to ensure that: the starting dose of 6 mgin all patients will be administered in the evening on days 1 and 2,followed by AM administration for the remainder of week 1 (if bodyweight is <40 kg); study drug should be swallowed whole and taken withfood; subsequent daily doses of 12 mg and higher will be administeredtwice daily in 2 divided doses, approximately 8 to 10 hours apart duringthe day; a minimum of 6 hours should elapse between doses; if a patientmisses a dose, and it is within 6 hours of the next dose, the misseddose should be skipped; if patients experience insomnia while taking theinitial 6-mg dose in the evening, they may switch to taking it as amorning dose for 2 days; after week 1, dose increases should not occurmore frequently than every 5 days; and dose reductions, if required,should be in increments of 6 mg.

Blinding and Randomization. Patients will be randomly assigned toreceive treatment with deutetrabenazine or matching placebo in a 1:1ratio.

Expected Results. It is expected that administration of a tolerableamount of deutetrabenazine, between 6 and 48 mg, in the above study inTourette syndrome patients will: reduce total tic severity, both motorand phonic/vocal tics, impairment, and/or global severity scores,improve quality of life, overall life satisfaction, and/or patient orclinical global impression of change, and improve (lengthen) tic-freeinterval. It is expected that safety will be consistent with what hasbeen observed in previous studies.

Long-Term Open-Label Phase 3 Study of Safety and Efficacy in TS Patients

Purpose. The primary objective of this study is to evaluate the safetyand tolerability of long-term therapy with deutetrabenazine; thesecondary objective is to evaluate efficacy.

Study Design. The study will include male and female patients with a ticassociated with Tourette syndrome (TS) who have previously completedparticipation in either of the above clinical studies ofdeutetrabenazine.

Screening. Informed consent/assent will be obtained before any studyprocedures are performed. Patients who have been off study drug forseveral months at the time of enrollment, and who are stable from amedical and psychiatric standpoint, will undergo a screening evaluationas described above in the randomized study. To reduce patient burden,some data collected in the randomized study above will be used toprovide corresponding data in this open label study. Patients may berescreened at the discretion of the medical monitor. Inclusion andexclusion criteria will be similar to those discussed above for therandomized trial, with the exception that participation in either of thetrials above is an inclusion, and not an exclusion, criterion, and thatdata regarding disqualifying DSM-V diagnoses may be obtained from thescreening visit of the randomized study.

Baseline visit. For patients enrolled in the randomized study above, thebaseline visit will occur simultaneously with the week 13 visit of thatstudy. Week 13 assessments specified for that are also specified for thebaseline visit of that study need not be repeated. For all patients, thebaseline visit will occur on the same day as the scheduled first dose ofthe study drug (day 1). For patients with clinically significantlaboratory abnormalities at week 12 in the randomized study above, theweek 13 value will serve as baseline in this study. Rollover for suchpatients must be approved by the medical monitor and may be delayed.

Titration Period (7 weeks). As patients from the pilot study will havebeen off study drug for several months at the time of enrollment, andsince patients from the randomized study will have discontinued studydrug or placebo for 1 week, all patients will undergo dose titration inthis study. Patients will receive 6 mg of deutetrabenazine with food onthe evening of day 1.

Maintenance Period (47 weeks). At the end of the titration period, thepatient's initial dose for the maintenance period will be established.Dose adjustments of deutetrabenazine (upward or downward) may be madeduring the maintenance period, if necessary, but not more often thanevery 5 days and only in increments of 6 mg. Dose adjustments should bemade based on all available information, including the patient andcaregiver/adult reports of adverse events and tic reduction, theclinical assessment of safety and efficacy by the investigator, thepatient's weight and CYP2D6 medication status, and information from therating scales. During the maintenance period, in-person (in-clinic)study visits will be scheduled at weeks 8, 15, 28, 41, and 54 forassessments of safety and efficacy. At week 54, patients will undergo acomplete evaluation as above in the randomized trial.

Washout and follow-up. All patients will discontinue study drug at theweek 54 visit and will return 1 week later (week 55) for evaluation ofsafety and tic reduction. Patients will have a follow-up telephonecontact for safety evaluation 1 week after the end of the washout period(2 weeks after their last dose of study drug [week 56]).

Dose regimen. Study drug will be administered as above for therandomized trial.

Study Endpoints. Safety endpoints will be as above in the randomizedstudy. Efficacy endpoints will include the Primary and SecondaryEfficacy Endpoints as above in the randomized study, with a goal ofreducing severity of motor and phonic/vocal tics. Exploratory endpointsbe as above in the randomized study, from baseline to each visit.

Expected Results. It is expected that administration of a tolerableamount of deutetrabenazine, between 6 and 48 mg, in the above study inTourette syndrome patients will: reduce total tic severity, both motorand phonic/vocal tics, impairment, and/or global severity scores,improve quality of life, overall life satisfaction, and/or patientglobal impression of severity or clinical global impression of change,and improve (lengthen) tic-free interval. It is expected that safetywill be consistent with what has been observed in previous studies.

QT Prolongation

Drug-drug interactions in the treatment of patients with HD and otherdisorders involving abnormal involuntary movement may also be a seriousconcern. Depression is a common comorbidity in HD and patients are oftentreated with selective serotonin reuptake inhibitors (SSRIs), includingcitalopram and escitalopram, that have a risk for QT prolongation.Additionally, owing to frequent behavioral abnormalities, severalstudies indicated that patients with HD often receive treatment withantipsychotics (one-quarter up to two-thirds of patients of HD havereceived antipsychotics. Antipsychotics are known to prolong the QTinterval. According to FDA guidance, prolongation of the QT interval canfavor the development of cardiac arrhythmias, such as torsade depointes, which can degenerate into ventricular fibrillation and lead todeath. Per the United States prescribing information, tetrabenazineshould not be used in conjunction with agents known to prolong the QTinterval.

Study Design. Given the known risk for tetrabenazine to increase the QTinterval, a TQT study of deutetrabenazine, which included tetrabenazineas a treatment arm, was conducted in 48 healthy volunteers. This was asingle-center, randomized, double-blind, placebo- andpositive-controlled six-period crossover study to evaluate the effectsof low-dose (12 mg) and high-dose (24 mg) deutetrabenazine on cardiacrepolarization, based on placebo-corrected, time-matched changes frombaseline in the QTcF interval. Assay sensitivity was established byusing moxifloxacin 400 mg as the positive control.

The key outcome measure was to determine the effect of single doses ofdeutetrabenazine on the QTc interval. A 50 mg dose of tetrabenazine wasselected as this was the maximal dose employed in the TQT study fortetrabenazine and resulted in the Warning and Precaution in the productlabel. A 24-mg dose of deutetrabenazine was selected as it providescomparable systemic exposure (AUC) to 50 mg of tetrabenazine, but with alower peak concentration (Cmax).

Results. For deutetrabenazine, 12-mg and 24-mg doses led toplacebo-corrected time-matched maximal increases in QTc of 2.8 ms and4.5 ms, respectively. For deutetrabenazine, the placebo-corrected changefrom baseline in QTcF and the upper bound of the two-sided 90%confidence interval was below the threshold of regulatory concern (5 ms)for both dose levels. In contrast, the maximum time-matched,placebo-adjusted change from baseline in QTcF for tetrabenazine 50 mgwas 7.6 ms, consistent with the tetrabenazine prescribing information.Results are given below in Table 25.

TABLE 25 Maximum Placebo-Adjusted Change from Baseline in QTcF withdeutetrabenazine and Tetrabenazine Tetra- Moxi- DTBZ DTBZ benazinefloxacin Parameter 12 mg 24 mg 50 mg 400 mg Placebo-Adjusted 2.8 4.5 7.614.0 Change from Baseline (ms) 90% 2-sided Confidence (0.7, 4.8) (2.4,6.5) (5.6, 9.5) (11.9, 16.0) Interval

In the table above, ΔΔQTcF is defined as the difference between theleast squares mean change from baseline for the active drug and placebo.deutetrabenazine was compared with deutetrabenazine placebo(administered under fed conditions) and tetrabenazine was compared withtetrabenazine placebo (administered under fasted conditions). Themaximal ΔΔQTcF was observed at the 8-hour time point fordeutetrabenazine and the 3-hour time point for tetrabenazine. The upperlimit of the 95% one-sided confidence interval is the upper limit of the90% 2-sided confidence interval.

Conclusion. These results support the fact that the differentiatedpharmacokinetic profile and lower Cmax associated with deutetrabenazinecompared with tetrabenazine improves the safety profile ofdeutetrabenazine by reducing the risk for life-threatening arrhythmias.

From the foregoing description, one skilled in the art can ascertain theessential characteristics of this invention, and without departing fromthe spirit and scope thereof, can make various changes and modificationsof the invention to adapt it to various usages and conditions.

What is claimed is:
 1. A method of transitioning a human fromtetrabenazine to deutetrabenazine for the tardive dyskinesia,comprising: a) discontinuing a daily amount of tetrabenazine; and b)administering an initial daily amount of deutetrabenazine the next dayto the human, wherein the daily amount of tetrabenazine is 12.5 mg andthe initial total daily amount of deutetrabenazine is 6 mg; or whereinthe daily amount of tetrabenazine is 25 mg and the initial total dailyamount of deutetrabenazine is 12 mg; or wherein the daily amount oftetrabenazine is 37.5 mg and the initial total daily amount ofdeutetrabenazine is 18 mg; or wherein the daily amount of tetrabenazineis 50 mg and the initial total daily amount of deutetrabenazine is 24mg; or wherein the daily amount of tetrabenazine is 62.5 mg and theinitial total daily amount of deutetrabenazine is 30 mg; or wherein thedaily amount of tetrabenazine is 75 mg and the initial total dailyamount of deutetrabenazine is 36 mg; or wherein the daily amount oftetrabenazine is 87.5 mg and the initial total daily amount ofdeutetrabenazine is 42 mg; or wherein the daily amount of tetrabenazineis 100 mg and the initial total daily amount of deutetrabenazine is 48mg.
 2. The method of claim 1, wherein the initial daily amount ofdeutetrabenazine is 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, 42 mg, or 48 mgand the initial daily amount of deutetrabenazine is administered in twodoses.
 3. The method of claim 2, wherein: the first dose is 6 mg and thesecond dose is 6 mg; the first dose is 9 mg and the second dose is 9 mg;the first dose is 12 mg and the second dose is 12 mg; the first dose is15 mg and the second dose is 15 mg; the first dose is 18 mg and thesecond dose is 18 mg; the first dose is 21 mg and the second dose is 21mg; or the first dose is 24 mg and the second dose is 24 mg.
 4. Themethod of claim 3, further comprising: c) after about one week,determining the degree of control of abnormal involuntary movementachieved with the initial daily amount of the deutetrabenazine and thetolerability of the initial daily amount of the deutetrabenazine; and d)increasing the daily amount of the deutetrabenazine upward by 6 mg/dayto a subsequent daily amount of the deutetrabenazine if thetransitioning does not result in at least a maintenance of choreacontrol and the initial daily amount is tolerable.
 5. The method ofclaim 4, further comprising: e) after about one week, repeating steps c)and d) in those humans wherein abnormal involuntary movement is reducedand the daily amount of deutetrabenazine is tolerated.
 6. The method ofclaim 5, further comprising: decreasing the amount of deutetrabenazineby 6 mg/day to a subsequent daily amount in those humans wherein anysubsequent daily amount is not tolerated.
 7. The method of claim 5,further comprising repeating step e) until the degree of control ofabnormal involuntary movement is adequate and the daily amount ofdeutetrabenazine is tolerable.
 8. The method of claim 1, wherein theinitial daily amount of deutetrabenazine is 12 mg, 18 mg, 24 mg, 30 mg,36 mg, or 42 mg, further comprising: c) after about one week,determining the degree of control of abnormal involuntary movementachieved with the initial daily amount of the deutetrabenazine and thetolerability of the initial daily amount of the deutetrabenazine; and d)increasing the daily amount of the deutetrabenazine by 6 mg/day to asubsequent daily amount in those humans wherein the transitioning doesnot result in at least a maintenance of control of abnormal involuntarymovement and the initial daily amount is tolerable.
 9. The method ofclaim 8, wherein the subsequent daily amount is 12 mg, 18 mg, 24 mg, 30mg, 36 mg, or 42 mg, further comprising: e) after about one week,repeating steps c) and d) in those patients wherein abnormal involuntarymovement is reduced and the daily amount of deutetrabenazine istolerated
 10. The method of claim 9, wherein the daily amount is 18 mg,24 mg, 30 mg, 36 mg, or 42 mg, further comprising repeating step e)until the degree of control of abnormal involuntary movement is adequateand the daily amount of deutetrabenazine is tolerable.
 11. The method ofclaim 10, wherein the total maximum daily dose is 48 mg.
 12. The methodof claim 10, where in the total maximum daily dose is 36 mg.
 13. Themethod of claim 12, wherein the human is concurrently receiving a strongCYP2D6 inhibitor.
 14. The method of claim 13, wherein the strong CYP2D6inhibitor is fluoxetine, paroxetine, bupropion, quinidine, cinacalcet,or ritonavir.
 15. The method of claim 14, wherein the strong CYP2D6inhibitor is paroxetine, fluoxetine, or bupropion.
 16. The method ofclaim 1, wherein the daily amount of tetrabenazine is 12.5 mg and theinitial total daily amount of deutetrabenazine is 6 mg.
 17. The methodof claim 1, wherein the daily amount of tetrabenazine is 25 mg and theinitial total daily amount of deutetrabenazine is 12 mg.
 18. The methodof claim 17, wherein the initial total daily amount of deutetrabenazineis administered in two doses, wherein the first dose is 6 mg and thesecond dose is 6 mg.
 19. The method of claim 1, wherein the daily amountof tetrabenazine is 37.5 mg and the initial total daily amount ofdeutetrabenazine is 18 mg.
 20. The method of claim 19, wherein theinitial total daily amount of deutetrabenazine is administered in twodoses, wherein the first dose is 9 mg and the second dose is 9 mg. 21.The method of claim 1, wherein the daily amount of tetrabenazine is 50mg and the initial total daily amount of deutetrabenazine is 24 mg. 22.The method of claim 21, wherein the initial total daily amount ofdeutetrabenazine is administered in two doses, wherein the first dose is12 mg and the second dose is 12 mg.
 23. The method of claim 1, whereinthe daily amount of tetrabenazine is 62.5 mg and the initial total dailyamount of deutetrabenazine is 30 mg.
 24. The method of claim 23, whereinthe initial total daily amount of deutetrabenazine is administered intwo doses, wherein the first dose is 15 mg and the second dose is 15 mg.25. The method of claim 1, wherein the daily amount of tetrabenazine is75 mg and the initial total daily amount of deutetrabenazine is 36 mg.26. The method of claim 25, wherein the initial total daily amount ofdeutetrabenazine is administered in two doses, wherein the first dose is18 mg and the second dose is 18 mg.
 27. The method of claim 1, whereinthe daily amount of tetrabenazine is 87.5 mg and the initial total dailyamount of deutetrabenazine is 42 mg.
 28. The method of claim 27, whereinthe initial total daily amount of deutetrabenazine is administered intwo doses, wherein the first dose is 21 mg and the second dose is 21 mg.29. The method of claim 1, wherein the daily amount of tetrabenazine is100 mg and the initial total daily amount of deutetrabenazine is 48 mg.30. The method of claim 29, wherein the initial total daily amount ofdeutetrabenazine is administered in two doses, wherein the first dose is24 mg and the second dose is 24 mg.